The Global Lipids Genetics Consortium (GLGC) is a world-wide collaboration of investigators dedicated to understanding the genetic etiology of quantitative lipid traits.
Department of Computational Medicine and Bioinformatics,
University of Michigan, Ann Arbor, MI, USA
Cardiovascular Research Center and Center for Human Genetic Research,Massachusetts General Hospital, Boston, Massachusetts, USA;Broad Institute,Cambridge, Massachusetts, USA;Department of Medicine,Harvard Medical School, Boston, Massachusetts, USA
The following cohorts have contributed to GLGC efforts:
Metabochip data were received from PARC and MORGAM, but were excluded from the meta-analysis because of sample overlap and failure to pass quality control checks.
ADVANCE is an epidemiological case-control study of genetic and non-genetic determinants of coronary artery disease (CAD) that started in 2000 as a collaborative effort between researchers at Stanford University and Kaiser Permanente of Northern California (KPNC)2. Between October 2001 and December 2003, a total of 3,179 subjects from KPNC were enrolled into three case groups and two control groups. A multi-ethnic subset of ~520 cases underwent GWAS in 2007 along with a set of controlsfrequency-matched to cases by age and sex. All remaining older onset cases (n = 974) and older controls (n =705) of white/European ancestry underwent Metabochipgenotyping in 2010. Included in this analysis are all controls not on lipid altering therapy at the time of determination of serum lipid levels.
2. Assimes, T.L. et al. Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Hum Mol Genet17, 2320-8 (2008).Back to top
AMC-PAS is aprospective study cohort recruited from the Academic Medical Centre Amsterdam that consists of patients with Premature AtheroSclerosis (PAS), defined as symptomatic CAD before the age of 51 years, or MI, coronary revascularization, or evidence of at least 70% stenosis in a major epicardial artery3. The total sample size at time of genotyping was 1,089; only cases with sufficient good quality DNA were included.
3. Samani, N.J. et al. Large scale association analysis of novel genetic loci for coronary artery disease. Arterioscler Thromb Vasc Biol29, 774-80 (2009).Back to top
The Old Order Amish individuals included in this study were participants of several ongoing studies of cardiovascular health carried out at the University of Maryland among relatively healthy volunteers from the Old Order Amish community of Lancaster County, PA and their family members4,5. The 1,200 subjects on whom the Metabochip was genotyped were recruited between 2002 and 2006 and examined at the Amish Research Clinic in Strasburg, PA.
4. Mitchell, B.D. et al. The genetic response to short-term interventions affecting cardiovascular function: rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study. Am Heart J155, 823-8 (2008).
5. Post, W. et al. Determinants of coronary artery and aortic calcification in the Old Order Amish. Circulation115, 717-24 (2007).Back to top
The 1958 British Birth Cohort was initiated as a study of perinatal mortality focusing on just over 17,000 births in England, Wales, and Scotland, during one week in 1958, with the aim of identifying social and obstetric factors linked to stillbirth and neonatal death6-8. The individuals were followed into adult life, with a biomedical survey of the cohort conducted when they were aged 44-45 years. The survey included anthropometric measurements, blood sampling for lipids, and blood pressure measurements. The sample comprises 5,639 individuals of white European ethnicity, of which 2,136 were analyzed (http://www.b58cgene.sgul.ac.uk/collection.php).
6. Power, C. & Elliott, J. Cohort profile: 1958 British birth cohort (National Child Development Study). Int J Epidemiol35, 34-41 (2006).
7. Strachan, D.P. et al. Lifecourse influences on health among British adults: effects of region of residence in childhood and adulthood. Int J Epidemiol36, 522-31 (2007).
8. Atherton, K., Fuller, E., Shepherd, P., Strachan, D.P. & Power, C. Loss and representativeness in a biomedical survey at age 45 years: 1958 British birth cohort. J Epidemiol Community Health62, 216-23 (2008).Back to top
The purpose of the study is to gather information about prevalence of diabetes and cardiovascular diseases and of the risk factors associated with these within the Finnish population9. The survey assists in the evaluation of the effects of the national type 2 diabetes prevention plan. The study sample consists of 4,500 people randomly selected from the Finnish population register between the ages of 45 and 74 years and living in one of the three hospital districts chosen for the study: South Ostrobothnia, Central Finland, and Pirkanmaa.
9. Kotronen, A. et al. Non-alcoholic and alcoholic fatty liver disease - two diseases of affluence associated with the metabolic syndrome and type 2 diabetes: the FIN-D2D survey. BMC Public Health10, 237 (2010).Back to top
The deCODE lipid study includes lipid measurements from Icelanders recruited through various genetic studies at deCODE, primarily cardiovascular studies10. The measurements were done between the years 1987 and 2010. For the current analysis we excluded individuals using lipid lowering drugs. Genotypes and lipidmeasurements were available for 15,612 Icelanders. The study was approved by the Icelandic Data Protection Commission and the National Bioethics Committee. All study participants signed informed consent and donated blood samples. Personal identities were encrypted by a third party system provided by the Icelandic Data Protection Commission.
10. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science316, 1491-3 (2007).Back to top
DIAGEN is a large, prospective study of diabetes genetics that began in 1997 and seeks to understand the genetic causes of diabetes development; 6,282 individuals have been studied to date11. DIAGEN recruits and phenotypes individuals at high risk of T2D; 3,611 individuals from German families with a history of T2D, obesity, or dyslipoproteinemia have been studied to date from Dresden and surrounding areas.
11. Schwarz, P.E. et al. Hypoadiponectinemia is associated with progression toward type 2 diabetes and genetic variation in the ADIPOQ gene promoter. Diabetes Care29, 1645-50 (2006).Back to top
DILGOM consists of 5,025 individuals who took part in the larger FINRISK 2007 collection12. The DILGOM sample was collected to study in greater detail the components affecting obesity and metabolic syndrome.
12. Vartiainen, E. et al. Thirty-five-year trends in cardiovascular risk factors in Finland. Int J Epidemiol39, 504-18 (2010).Back to top
DPS is a prospective randomized controlled trial aimed at preventing the progression from IGT to diabetes13. The original DPS was initiated in 1993. A total of 522 middle-aged, overweight subjects with IGT at baseline were randomized into either a lifestyle intervention or a standard-care control group. They were followed for occurrence of diabetes until the year 2000, when the first interim analysis of the data was carried out as originally planned. At this point, the randomized trial was prematurely terminated due to markedly lower diabetes incidence rate in the lifestyle intervention group as compared to the control group. Since the termination of the randomized phase of the DPS, the original cohorts are no longer offered different treatments. However, all participants are monitored with yearly visits for long-term development of type 2 diabetes and complications.
13. Tuomilehto, J. et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med344, 1343-50 (2001).Back to top
DR's EXTRA is a 4-year randomized controlled trial on the health effects of aerobic and resistance exercise training and a diet with lowsaturated fat, highunsaturatedfat, and highfiber in a population sample of middle-aged and older men and women14. The target population was a representative sample of 3,000 individuals (1,500 men, 1,500 women) who lived in the city of Kuopio in Finland and who were 55-74 years of age in 2002, when they were randomly selected from the national population register. Of these individuals, 2,062 were willing to participate and 1,479 (72%) participated in the baseline examinations in 2005-2006. 1,410 individuals were randomly allocated into one of the six study groups, each of which included about 235 persons.
14. Kouki, R. et al. Diet, fitness and metabolic syndrome - The DR's EXTRA Study. Nutr Metab Cardiovasc Dis (2010).Back to top
EASis a prospective study of 1,592 men and women whose age at baseline ranged from 55 to 74 years15. The population was selected at random, in 5-year age bands, from 10 general practices spread socioeconomically across the city of Edinburgh, Scotland. A large number of biomarkers and phenotypes, focusing predominantly on putative vascular risk factors, have been measured. To identify all deaths, participant records were flagged at the UK NHS Central Registry. To obtain details of possible non-fatal events, information was sought from general practitioners, hospitals, the Information Services Division of NHS Scotland and by annual questionnaire to the subjects themselves. All cardiovascular events and deaths were further investigated using hospital or general practitioner records. The study was approved by the Lothian Health Board Ethics Committee and informed consent was obtained from each participant.
15. Fowkes, F.G. et al. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol20, 384-92 (1991).Back to top
The Estonian cohort is from the population-based biobank of the Estonian Genome Project of University of Tartu (EGCUT)16. The project is conducted according to the Estonian Gene Research Act, and all participants have signed the broad informed consent. The current cohort size is > 51,515, 18 years of age and older, which reflects closely the age distribution in the adult Estonian population. Subjects are recruited by the general practitioners (GP) and physicians in the hospitals were randomly selected from individuals visiting GP offices or hospitals. Each participant filled out a computer-assisted personal interview during 1-2 hours at a doctor's office, including personal data (place of birth, place(s) of living, nationality. etc.), genealogical data (three generation family history), educational and occupational history, and lifestyle data (physical activity, dietary habits, smoking, alcohol consumption, women's health, quality of life). For the current study, 2,770 individuals were genotyped with Metabochip; 1,072 of these had lipids data available.
16. Nelis, M. et al. Genetic structure of Europeans: a view from the North-East. PLoS One4, e5472 (2009).Back to top
The Ely study commenced in 1990 as a prospective population-based cohort study of the etiology and pathogenesis of type 2 diabetes and related metabolic disorders. Study aims are: 1) understanding the pathogenesis of type 2 diabetes in a Caucasian population through longitudinal examination of people free of diabetes at baseline; 2) determining early markers of future risk of progression of glucose intolerance and providing the means to identify populations at high risk of diabetes; and 3) quantifying and specifying the role of key exposures in adult life, particularly diet and physical activity17.
17. Williams, D.R. et al. Undiagnosed glucose intolerance in the community: the Isle of Ely Diabetes Project. Diabet Med12, 30-5 (1995).Back to top
EPIC was designed to investigate the relationships between diet, nutritional status, lifestyle and environmental factors and the incidence of cancer and other chronic diseases. EPIC is a large study of diet and health having recruited 520,000 individuals18,19.
18. Day, N. et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br J Cancer80 Suppl 1, 95-103 (1999).
19. Harding, A.H. et al. Dietary fat and the risk of clinical type 2 diabetes: the European prospective investigation of Cancer-Norfolk study. Am J Epidemiol159, 73-82 (2004).Back to top
Fenland is a population-based study of lifestyle and health. The study will investigate the influence of diet, lifestyle, and genetic factors on the development of diabetes and obesity. The participants are from the general population in the East Cambridgeshire and Fenland area and were born between 1950 and 1975.Back to top
The purpose of the FINCAVAS is to construct a risk profile - using genetic, haemodynamic, and electrocardiographic (ECG) markers - of individuals at high risk of cardiovascular diseases, events, and deaths20. All patients scheduled for an exercise stress test at Tampere University Hospital and willing to participate were recruited between October 2001 and December 2007. The final number of participants is 4,567. In addition to repeated measurement of heart rate and blood pressure, digital high-resolution ECG at 500 Hz is recorded continuously during the entire exercise test, including the resting and recovery phases. About 20% of the patients are examined with coronary angiography. Genetic variations known or suspected to alter cardiovascular function or pathophysiology are analyzed to elucidate the effects and interactions of these candidate genes, exercise, and commonly used cardiovascular medications. Genotyping has been done with the Metabochip for 2,795 participants. After exclusions, both genotype and lipid data were available for 1,201 participants.
20. Nieminen, T. et al. The Finnish Cardiovascular Study (FINCAVAS): characterising patients with high risk of cardiovascular morbidity and mortality. BMC Cardiovasc Disord6, 9 (2006).Back to top
CAD patients were randomly assigned an early invasive or non-invasive treatment strategy with placebo-controlled long-term low-molecular-mass heparin (dalteparin) for 3 months as part of a clinical trial21. Total sample size of cases is 3,489. Healthy controls (N=500) were selected to match in age and sex to the cases. In total, 2,963 individuals have been analyzed (N cases = 2,552 N controls = 411).
21. Wallentin, L. et al. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. FRISC II Investigators. Fast Revascularisation during Instability in Coronary artery disease. Lancet356, 9-16 (2000).Back to top
FUSION2 includes subjects chosen from the following studies: Dehko 2D (D2D) 2004: a population-based study to screen individuals regarding T2D risk and to prevent T2D development; Finrisk 1987: an early round of the 5-yearly Finrisk national population-based health surveys; Finrisk 2002: a population-based survey of non-communicable diseases in ≥ 13,000 individuals aged 25-74 years living in 80 communities of Finland; Action LADA: a study of latent autoimmune diabetes in adults (LADA)22. Action LADA investigators screened individuals aged 30-69 years with recently-diagnosed diabetes and identified 373 T2D cases who agreed to participate in FUSION; Health 2000: a population-based study of people aged .30 years from throughout Finland; Savitaipale Diabetes Study: a study of diabetes in the town of Savitaipale in eastern Finland.
22. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science316, 1341-5 (2007).Back to top
GLACIER is an ongoing population-based prospective cohort study comprising 19,547 adults from the northern Swedish county of Västerbotten, nested within the Northern Sweden Health and Disease Study23. All GLACIER participants underwent detailed health and lifestyle examinations as part of the Västerbotten Intervention Programme (VIP), an ongoing population-wide project focused on type 2 diabetes, cardiovascular disease, and common cancers. Since 1985, all residents of the county aged 40, 50, and 60 years have been invited to visit their primary health care centers for clinical examinations according to a standardized protocol. Baseline examinations of GLACIER participants were undertaken from 1985 through 2004. In the present study, 5,764 individuals were included in the analysis.
23. Renstrom, F. et al. Genetic predisposition to long-term nondiabetic deteriorations in glucose homeostasis: Ten-year follow-up of the GLACIER study. Diabetes60, 345-54 (2011).Back to top
A high quality resource, initially funded by the Wellcome Trust and supported by Diabetes UK, has been created with successful recruitment of consented patients with type 2 diabetes and matching controls (non diabetics) throughout Tayside24.
24. Kimber, C.H. et al. TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels. Diabetologia50, 1186-91 (2007).Back to top
The HUNT study is a large population-based health study in Nord-Trøndelag county, central Norway (population 127,000). HUNT 2 was carried out in 1995-1997; data were collected through questionnaires, clinical exam, and blood and urine samples. 74,000 individuals (71%) participated.Back to top
IMPROVE is a cohort of European subjects with .3 classical CVD risk factors, recruited from seven centers in five countries25. Of 3,418 subjects with genotyping and detailed ultrasonic phenotyping of carotid inter-media thickness, 1,769 subjects were included in this study.
25. Baldassarre, D. et al. Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study. Eur Heart J31, 614-22 (2010).Back to top
KORA is a series of independent population-based epidemiological surveys and follow-up studies of participants living in the region of Augsburg, Southern Germany26. All participants are residents of Germany. In KORA S3, 4,856 subjects have been examined. 3,184 subjects participated in a 10-year follow-up examination of S3 in 2004/05. The present study includes data of 2,816 individuals of the follow-up study KORA F3. All participants gave signed informed consent. The local ethics committee has approved the studies.
26. Wichmann, H.E., Gieger, C. & Illig, T. KORA-gen--resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen67 Suppl 1, S26-30 (2005).Back to top
KORAis a series of independent population-based epidemiological surveys and follow-up studies of participants living in the region of Augsburg, Southern Germany26. All participants are residents of Germany. In the KORA S4 study, 4,261 subjects have been examined. 3,080 subjects participated in a 10-year follow-up examination of S4 in 2006-2008. The present study includes data of 2,678 individuals of the follow-up study KORA F4. All participants gave signed informed consent. The local ethics committee has approved the studies.Back to top
LURIC includes 3,316 consecutive white patients of Caucasian origin (17 to 92 years of age) hospitalized for coronary angiography between June 1997 and May 200127. Clinical indications for angiography were chest pain or non-invasive tests consistent with myocardial ischemia. To limit clinical heterogeneity, individuals suffering from acute illness other than acute coronary syndromes, chronic non-cardiac diseases and a history of malignancy within the five past years were excluded. For this study, 1,506 samples were included in the analysis.
27. Winkelmann, B.R. et al. Rationale and design of the LURIC study--a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics2, S1-73 (2001).Back to top
Prospective observational population-based study with a baseline examination 1991-1996 (n = 28,098) and follow ups of mortality and morbidity by means of registries28. The main focus is on cancer and cardiovascular disease.
28. Berglund, G., Elmstahl, S., Janzon, L. & Larsson, S.A. The Malmo Diet and Cancer Study. Design and feasibility. J Intern Med233, 45-51 (1993).Back to top
The METSIM study aims to investigate the metabolic syndrome, type 2 diabetes, cardiovascular disease, and cardiovascular risk factors29. It is an ongoing study of men aged 50 to 70 years, randomly selected from the population registry of the town of Kuopio, in Eastern Finland.
29. Stancakova, A. et al. Changes in insulin sensitivity and insulin release in relation to glycemia and glucose tolerance in 6,414 Finnish men. Diabetes58, 1212-21 (2009).Back to top
NFBC1986 is a longitudinal one-year birth cohort study from an unselected population. The cohort included all the mothers (N = 9,362) with children whose expected date of birth fell between July 1, 1985 and June 30, 1986 in the two northernmost provinces of Finland (Oulu and Lapland). Altogether 9,479 children were born into the cohort, 9,432 of them live-born. In the 15/16-year follow-up study, blood samples were taken from 6,400 individuals of whom 4,900 were genotyped.Back to top
The Medical Research Council National Survey of Health and Development (NSHD), MRC 1946 Study30. This is an ongoing prospective birth cohort study consisting of all births in England, Scotland, and Wales in one week in March 1946. The sample includes single, legitimate births whose fathers were in non-manual or agricultural occupations and a randomly selected one in four of all others, whose fathers were in manual labor. The original cohort, now 62 years of age, comprised 2,547 women and 2,815 men who have been followed up > 20 times since birth. The data collected to date include cognitive function, physical, lifestyle and anthropomorphic measures as well as blood analytes, and other measures. Through MRC Unit funding, the cohort is currently undergoing a particularly intensive phase of clinical assessment and biological sampling, with blood and urine sampling and analysis, cardiac and vascular imaging (http:www.nshd.mrc.ac.uk).
30. Wadsworth, M., Kuh, D., Richards, M. & Hardy, R. Cohort Profile: The 1946 National Birth Cohort (MRC National Survey of Health and Development). Int J Epidemiol35, 49-54 (2006).Back to top
Participants were randomly sampled from all men and women aged 70 years living in Uppsala County in 2001 (www.medsci.uu.se/PIVUS)31. Of the 2,025 individuals invited, 1,016 participated. Participants underwent a medical examination including a detailed questionnaire on lifestyle and socioeconomic factors, fasting blood sampling, blood pressure measurement and anthropometric measurements, as previously described.18 Blood and plasma samples were frozen until analysis, and blood tests performed included a wide variety of traditional and more recent CVD risk factors, along with DNA extraction. In addition, individuals have undergone extensive phenotyping including whole body MRI, echocardiography, endothelial function measurements, carotid ultrasound, DXA, and spirometry.
31. Ingelsson, E., Hulthe, J. & Lind, L. Inflammatory markers in relation to insulin resistance and the metabolic syndrome. Eur J Clin Invest38, 502-9 (2008).Back to top
The SardiNIA study is a cohort of 6,148 participants, aged 14-102 years, from four clustered towns in Sardinia; it includes 34,469 relative pairs32. Phenotype data are available on hundreds of traits. GWAS data has been collected on ~4,700 individuals and the entire sample has been genotyped with the Metabochip.
32. Pilia, G. et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet2, e132 (2006).Back to top
A case-control study recruited from the Stockholm region of Sweden. Controls subjects were matched (for age and geographical location) to subjects with MI. Of a total of 3,400 subjects, 2,973 were included in this study.Back to top
Four sub-studies within the Swedish Twin Register were utilized in current study, including Sex differences in health and aging (GENDER), Individual differences among the oldest-old (OCTO-Twin), and Swedish Adoption/Twin Study of Aging (SATSA)33. Similar examinations with both questionnaires and blood sampling were done in each study.
Information has been updated annually on mortality and morbidity using national registries, such as the Cause of Death Registry, the National Patient Registry, and the Prescribed Drug Registry. Different biomarkers have been measured, such as markers of inflammation, lipoproteins, fatty acid composition, glucose and insulin metabolism. We required overnight fasting before blood draw except for OCTO-Twin study.
33. Reynolds, C.A. et al. A survey of ABCA1 sequence variation confirms association with dementia. Hum Mutat30, 1348-54 (2009).Back to top
THISEAS is a case-control study designed to investigate the association between genetic and lifestyle environmental factors and the risk of coronary artery disease in adults34,35. Study participants were recruited from 8 hospitals and from Open Care Centers for the elderly in the region of Athens. Cases were subjects presenting with either ACS or stable CAD defined as > 50% stenosis in at least one of the three main coronary vessels assessed by coronary angiography. ACS was defined as acute MI or unstable angina corresponding to class III of the Braunwald classification. ACS patients have also undergone coronary angiography examination that verified the presence of significant stenosis. Controls were subjects with negative coronary angiography findings, or negative stress test, or subjects without symptoms of disease that were admitted at the same hospitals as cases and were free of any cardiovascular disease, cancer, or inflammatory diseases. Exclusion criteria for both study groups were renal or hepatic disease. The bioethics committee of Harokopio University approved the study and all participants gave their informed consent. Hematological, biochemical, and anthropometric measurements were conducted for all participants. Dietary assessment through a semi-quantitative food frequency questionnaire and physical activity data were collected through face-to-face interview by well trained scientists.
34. Theodoraki, E.V. et al. Fibrinogen beta variants confer protection against coronary artery disease in a Greek case-control study. BMC Med Genet11, 28 (2010).
35. Theodoraki, E.V. et al. ROS1 Asp2213Asn polymorphism is not associated with coronary artery disease in a Greek case-control study. Clin Chem Lab Med47, 1471-3 (2009).Back to top
The Tromsø is a prospective population-based study in the city of Tromsø in Northern Norway (population 64,000)36. There have been five study waves to date. The participation rate was > 75% each time; 38,164 adults have participated at least once. For Tromsø 4(1994), all inhabitants aged .25 years were invited and 27,159 (77%) participated.
36. Jacobsen, B.K., Eggen, A.E., Mathiesen, E.B., Wilsgaard, T. & Njolstad, I. Cohort profile: The Tromso Study. Int J Epidemiol (2011).Back to top
ULSAM was initiated as a health investigation focused on identifying metabolic risk factors for cardiovascular disease, to which all 50-year-old men living in Uppsala County, Sweden, in 1970-74 were invited37. Of these, 82% (2,322 men) participated in the investigation. The men have been investigated at the ages of 50, 60, 71, 77, 82, and 88 years. The examination performed at age 71 (in 1991-1995), when the DNA was collected, included medical examination, questionnaire, cognitive function testing, 7-day dietary assessment, anthropometric measurements, blood sampling (after an overnight fast), blood pressure measurement, 24-hour ambulatory blood pressure measurement, electrocardiography, echocardiography, OGTT, muscle biopsy, and euglycemic insulin clamp. Outcome data have been updated annually on mortality and morbidity using national registries, such as the Cause of Death Registry, the National Patient Registry, and the Prescribed Drug Registry. Many biomarkers have been measured, such as markers of inflammation/oxidation, lipoproteins, fatty acid composition, and glucose and insulin metabolism. Insulin sensitivity was determined using the euglycemic insulin clamp technique, with a slight modification; insulin was infused at a constant rate of 56 instead of 40 mU/(min*m2) to achieve nearly complete suppression of hepatic glucose output.
37. Ingelsson, E., Sundstrom, J., Arnlov, J., Zethelius, B. & Lind, L. Insulin resistance and risk of congestive heart failure. JAMA294, 334-41 (2005).Back to top
The Whitehall II Study recruited 10,308 participants (70% men) between 1985 and 1989 and involved 20 London-based civil service departments38. In this longitudinal study, clinical data were collected in phase 1 (1985-1988), phase 3 (1991-1993), phase 5 (1997-1999), and phase 7 (2003-2004). DNA was stored from phase 7 from > 6,000 participants. The study individuals are all well phenotyped for cardiovascular and other ageing related health outcomes.
38. Marmot, M. & Brunner, E. Cohort Profile: the Whitehall II study. Int J Epidemiol34, 251-6 (2005).Back to top
CLHNSis an on-going community-based study that began in 198339. The baseline survey randomly recruited 3,327 mother-child pairs from 17 urban and 16 rural areas from the Metropolitan Cebu area, the Philippines. Overnight fasting blood samples for biomarkers and DNA were obtained at the 2005 survey. In this study, 1,771 offspring samples were included in analysis.
39. Adair, L.S. et al. Cohort profile: the Cebu longitudinal health and nutrition survey. Int J Epidemiol40, 619-25 (2011).Back to top
The TaiChi consortium was formed through a collaborative effort between investigators based in the U.S. and Taiwan. The consortium's primary aim is to identify genetic determinants of atherosclerosis and diabetes related traits in East Asians and to fine-map validated loci identified in other race/ethnic groups.The main academic sites in Taiwan include Taipei and Taichung Veteran's General Hospitals (VGH), National Health Research Institute (NHRI), Tri-Service General Hospital (TSGH), and National Taiwan University Hospital (NTUH). The main U.S academic sites participating in the TaiChi consortium include Stanford University School of Medicine in Stanford, California; Hudson-Alpha Biotechnology Institute in Huntsville, Alabama; and Cedars-Sinai Medical Center (CSMC) in Los Angeles, California. There are 7 principal Taiwan based cohorts that make up the current TaiChi bio-resource with a total of 11,859 subjects in the current study. Each cohort is described in more detail in the supplementary text.
A total of 3,958 participants from AIDHS are from two different cohorts comprising 2,902 individuals from the Sikh Diabetes Study (SDS) and 1,056 migrant Asian Indians living in the US40,41. Of these, 1,516 subjects (800 males/ 716 females) available with genome-wide genotyping data (llumina's 660W-Quad BeadChip) were used in the present study. These individuals were recruited through public advertisements from Northern states of India including Punjab, Haryana, and Delhi. Both men and women aged 17-90 years participated. Individuals with non-Punjabi ancestry and non-Asian Indian ancestry were not enrolled. Normoglycemic control subjects were random individuals recruited from the same Asian Indian community as the patients, and matched for ethnicity and geographic location. Diagnoses of type 2 diabetes were confirmed by reviewing medical records for symptoms, use of medication, and measuring fasting glucose levels following the guidelines of the American Diabetes Association (2004)42. A medical record indicating either (1) a fasting plasma glucose level .7.0 mmol/L or .126 mg/dL after a minimum 12h fast or (2) a 2h post-glucose level (2h oral glucose tolerance test) .11.1mmol/L or .200 mg/dL on more than one occasion, combined with symptoms of diabetes confirmed the diagnosis. Impaired fasting glucose (IFG) is defined as a fasting blood glucose level .100 mg/dL (5.6 mmol/L) but .126 mg/dL (7.0 mmol/L). Impaired glucose tolerance (IGT) is defined as a 2h OGTT > 140mg dL (7.8mmol/L) but < 200mg /dL(11.1mmol/L).Subjects with IFG or IGT were excluded from this study. The 2h OGTTs were performed following the criteria of the World Health Organizations (WHO) (75 g oral load of glucose). The selection of normoglycemic controls was based on a fasting glycemia < 100.8 mg/dL or a 2h glucose < 141.0 mg/dL. Serum lipids (total cholesterol, LDL cholesterol, HDL cholesterol, VLDL cholesterol, and triglycerides) were quantified using standard enzymatic methods (Roche, Basel, Switzerland).All quantitative parameters were determined by following manufacturer's instructions using a Hitachi 902 auto-analyzer (Roche, Basel, Switzerland). All blood samples were obtained at the baseline visits. All participants signed a written informed consent for the investigations. The study was reviewed and approved by the University of Oklahoma Health Sciences Center's Institutional Review Board, as well as the Human Subject Protection Committees at the participating hospitals and institutes in India.
40. Sanghera, D.K. et al. Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk. BMC Med Genet9, 59 (2008).
41. Been, L.F. et al. Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: a study of 3,310 subjects from India and the US. BMC Med Genet12, 18 (2011).
42. Hammond, C.J., Andrew, T., Tat Mak, Y. & Spector, T.D. A Susceptibility Locus for Myopia in the Normal Population Is Linked to the PAX6 Gene Region on Chromosome 11: A Genomewide Scan of Dizygotic Twins. Am J Hum Genet75, 294-304 (2004).Back to top
PROMIS is an ongoing case-control study of acute myocardial infarction (MI) in urban Pakistan, which by mid-2009 included 5,500 MI cases and 5,500 controls43. Cases have typical ECG characteristics, a positive troponin test, and MI symptoms within the previous 24 hours. Controls are individuals frequency-matched to cases by sex and age (in 5 year bands) and identified in the same hospitals as the index cases. Controls have been recruited in the following order of priority: (i) visitors of patients attending the out-patient department; (ii) patients attending the out-patient department for routine non-cardiac complaints, or (iii) non-blood related visitors of index MI cases. A locally-piloted and validated epidemiological questionnaire has been administered to participants by medically qualified research officers that seeks > 200 items of information in relation to: ethnicity (eg, personal and paternal ethnicity, spoken language, place of birth and any known consanguinity); demographic characteristics; lifestyle factors (eg, tobacco and alcohol consumption, dietary intake, and physical activity); personal and family history of cardiovascular disease; and medication usage. PROMIS has received approval by the relevant research ethics committee of each of the institutions involved in participant recruitment. Informed consent has been obtained from each participant recruited into the study, including consent to use the samples in genetic, biochemical, and other analyses.
43. Saleheen, D. et al. The Pakistan Risk of Myocardial Infarction Study: a resource for the study of genetic, lifestyle and other determinants of myocardial infarction in South Asia. Eur J Epidemiol24, 329-38 (2009).Back to top
The FBPP GenNet study recruited European-American (N=1,497) and African American (N=1,101) participants at two field centers between 1995 and 2003, based on a hypertensive proband44. Non-Hispanic white subjects were recruited from Tecumseh, Michigan, and African American subjects were recruited from Maywood, Illinois. Probands were defined as individuals aged 18-50 years with blood pressures in the upper 20th to 25th percentile of the age/gender specific blood pressure distribution. Once the proband was identified, an attempt was made to enroll all siblings and parents of the proband, irrespective of their blood pressure or hypertension treatment status. Blood pressure measurements were carried out according to standard procedures in a sitting position after a resting period. Subjects were not allowed to smoke or drink coffee before the visit. The average of two manual BP measurements was used as the phenotype. DNA was available for 1,381 European American and 848 African-American participants (www.biostat.wustl.edu/fbpp/FBPP.shtml). The Hypertension Genetic Epidemiology Network recruited two types of participants (hypertensive sibships and random samples of subjects) in European American and African American samples. Recruitment of the study participants, including the hypertensive probands, was carried out at five field centers based largely on ongoing population based studies. For European Americans, HyperGEN recruited and characterized a total of 1,142 hypertensive subjects from 480 sibships, yielding a total of 992 self-reported sib-pairs, and a random sample of 472 biologically unrelated participants. For African Americans,HyperGEN recruited and characterized a total of 1,261 hypertensive subjects from 596 sibships yielding a total of 826 self-reported sib-pairs, and a random sample of 446 biologically unrelated African Americans (www.biostat.wustl.edu/fbpp/FBPP.shtml). Blood pressure measurements were carried out according to standard procedures in a sitting position after a resting period.
44. Multi-center genetic study of hypertension: The Family Blood Pressure Program (FBPP). Hypertension39, 3-9 (2002).Back to top
The Kingston GXE cohort was obtained from a survey conducted inKingston, Jamaica as part of a larger project to examine gene by environment interactions in the determination of blood pressure among adults 25-74 years45. The principal criterion for eligibility was a body mass index in either the top or bottom third of BMI for the Jamaican population. Participants were identified principally from the records of the Heart Foundation of Jamaica, a non-governmental organization based in Kingston, which provides low-cost screening services (height and weight, blood pressure, glucose, cholesterol) to the general public. Other participants were identified from among participants in family studies of blood pressure at the Tropical Metabolism Research Unit (TMRU) and from among staff members at the University of the West Indies, Mona.
45. Lettre, G. et al. Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project. PLoS Genet7, e1001300 (2011).Back to top
MRC/UVRI GPC is a population-based cohort study of > 18,000 people living within the Kyamulibwa sub-county of Kalungu District in rural south-west Uganda. The cohort was established in 1989 by the Medical Research Council (MRC) Programme on AIDS in Uganda to describe trends in the prevalence and incidence of HIV infection and their determinants in the general population. Today the study also aims to estimate the prevalence and distribution of cardiometabolic risks factors and diseases in the population. This cohort has GWAS data but only the SNPs overlapping with metabochip were included.Back to top
SEY recruited 494 participants, aged over 18 years, from 76 families of East African descent from the Republic of Seychelles (Indian Ocean), collected for the primary purpose of a candidate gene study of arterial hypertension46. Families were selected from a national register that includes all patients with hypertension. Families were selected if there were two or more full siblings with hypertension (defined as being on current antihypertensive treatment or having an average (6 measures) office systolic/diastolic blood pressure greater than or equal to 140/90 mm Hg). Participants were recruited from July 1999 until January 2002. Blood was collected in the morning between 7 am and noon after overnight fasting.
46. Bochud, M. et al. Heritability of renal function in hypertensive families of African descent in the Seychelles (Indian Ocean). Kidney Int67, 61-9 (2005).Back to top
Participants were recruited from Spanish Town, a stable, residential urban area neighboring the capital city of Kingston, Jamaica as part of the International Collaborative Study of Hypertension in Blacks (ICSHIB)47. A stratified random sampling scheme was used to recruit adult males and females aged 25-74 years from the general population. Spanish Town was chosen because its demographic make-up was broadly representative of Jamaica as a whole.
47. Cooper, R. et al. The prevalence of hypertension in seven populations of west African origin. Am J Public Health87, 160-8 (1997).Back to top
The study48 was initiated in 2002 to examine genetic susceptibility and gene/environment interactions related to disease and disability in old age. The AGES study is comprised of approximately 2,500 samples drawn from the Reykjavik Study, a population-based cohort comprised of individuals born between 1907 and 1935 and followed since 1967 by the Icelandic Heart Association.
48. Harris, T.B. et al. Age, Gene/Environment Susceptibility-Reykjavik Study: multidisciplinary applied phenomics. Am J Epidemiol. 165, 1076-1087 (2007).Back to top
The ARIC Study51 is a multi-center prospective investigation of atherosclerotic disease. White and African American men and women aged 45-64 years at baseline were recruited from four communities: Forsyth County, North Carolina; Jackson, Mississippi; suburban areas of Minneapolis, Minnesota; and Washington County, Maryland. A total of 15,792 individuals participated in the baseline examination in 1987-1989, with three triennial follow-up examinations. 7,841 white subjects were included in this analysis. Individuals known to be taking lipid-lowering medications and/or to have type 2 diabetes were excluded. Prevalent type 2 diabetes was defined as the presence of any of the following: a fasting blood glucose level of ≥ 126 mg/dL (7.0 mmol/L); a nonfasting blood glucose level of ≥ 200 mg/dL (11.1 mmol/L); selfreported physician diagnosis of type 2 diabetes; or pharmacologic treatment of diabetes in the past two weeks.
51. ARIC Investigators. Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am. J. Epidemiol. 129, 687-702 (1989).Back to top
Twin samples were drawn from the GenomEUtwin project52, which is comprised of the Danish, Dutch, Finnish, Italian, Norwegian, and Swedish national twin cohorts, an Australian twin cohort, and the UK-based TwinsUK cohort. The current study included monozygotic twin pairs from the Australian (MZGWAAUS; 449 pairs), Danish (MZGWA-DK; 142 pairs), Dutch (MZGWA-NLD; 289 pairs), Finnish (MZGWA-FIN; 137 pairs), Swedish (MZGWA-SWE; 297 pairs), and UK (MZGWA-UK; 457 pairs) cohorts. In each of the six twin cohorts, female monozygotic twin pairs were identified, lipid measurements were averaged for each pair, and genotype data for one of the individuals was used in the analysis.
52. Peltonen, L. GenomEUtwin: a strategy to identify genetic influences on health and disease. Twin Res. 6, 354-360 (2003).Back to top
The BLSA53 is an on-going prospective study that began in 1958 to investigate changes that occur with normal aging. The study consists of volunteers recruited primarily from the Washington, DC, and Baltimore, MD, areas. Genome-wide data were available for 1,230 participants. The analysis was restricted to 713 Caucasian individuals with lipid measurements.
53. Shock, R.C., Greulich, R.C. & Andres, R.A. Normal Human Aging: The Baltimore Longitudinal Study of Aging. NIH publication no. 84-2450, 45. Washington D.C., U.S. Government Printing Office (1984).Back to top
This study was part of the Wellcome Trust Case Control Consortium (WTCCC) and has been described previously54,55. The British 1958 Birth Cohort is a national population sample followed periodically from birth to age 44-45 years. The current analysis included 1,459 individuals that passed quality control criteria and had lipid measurements available.
54. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 447, 661-678 (2007).
55. Barrett, J.C. & et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703-707 (2009).Back to top
The CHS56 is a population-based cohort study of risk factors for coronary heart disease and stroke in adults ≥ 65 years conducted across four field centers. The original predominantly Caucasian cohort of 5,201 persons was recruited in 1989-1990 from random samples of the Medicare eligibility lists, and an additional 687 African-Americans were enrolled subsequently for a total sample of 5,888. DNA was extracted from blood samples drawn on all participants at their baseline examination in 1989-90. In 2007-2008, genotyping was performed at the General Clinical Research Center's Phenotyping/Genotyping Laboratory at Cedars-Sinai on 3,980 CHS participants who were free of cardiovascular disease at baseline, consented to genetic testing, and had DNA available for genotyping. To limit the possibility of confounding due to population structure, these analyses were limited to the 3,121 white participants with genotype data and lipid measurements.
56. Fried, L.P. et al. The Cardiovascular Health Study: design and rationale. Ann. Epidemiol. 1, 263-276 (1991).Back to top
In CoLaus57 study participants were randomly selected from a list of 56,694 individuals aged 35 to 75 years who were permanent residents of the City of Lausanne, Switzerland. Only individuals with four grandparents of European origin were included in the study. The CoLaus study was sponsored in part by GlaxoSmithKline, and all participants were duly informed about this sponsorship. Principal components were computed to adjust for population stratification using EIGENSOFT (http://genepath.med.harvard.edu/~reich/Software.htm). After using the Akaike Information Criterion (AIC) based stepwise model selection, the 3 principal components significant at P < 0.05 were included as covariates in the association analyses. A total of 5,253 participants with lipids measurements were included in this analysis.
57. Firmann, M. et al. The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC Cardiovasc. Disord. 8, 6 (2008).Back to top
The KORA surveys have been described in paper58,59. The third KORA survey (KORA S3, n=3,996) is a population-based sample from the general population of the South-German city of Augsburg and surrounding counties from 1994/1995. A subsample of 1,644 individuals from this survey with 10-year followup (KORA F3) information available was successfully genotyped (the KORA S3/F3 500K Study). All participants had a German passport and were of European origin. A total of 1,405 participants not on lipid-lowering therapy and with lipid measurements were included in this analysis.
58. Wichmann, H.E., Gieger, C. & Illig, T. KORA-genresource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen. 67 Suppl 1, S26-S30 (2008).
59. Heid, I.M. et al. Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys. J. Med. Genet. 42, e21 (2005).Back to top
The EPIC-Norfolk studies have been described in paper60,61. EPIC-Norfolk is an ongoing prospective cohort study of chronic diseases comprising 25,663 Norfolk residents, an ethnically homogenous European origin population aged 39-79 who were recruited from general practice registers between 1993 and 1997 for a first health examination. A total of 2,346 non-obese subjects were included in this analysis.
60. Day, N. et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br. J. Cancer. 80, 95-103 (1999).
61. Harding, A.H. et al. Dietary fat and the risk of clinical type 2 diabetes: the European Prospective Investigation of Cancer-Norfolk study. Am. J. Epidemiol. 159, 73-82 (2004).Back to top
The Fenland Study is a community-based cohort of individuals born between 1950 and 1975 and residing in East Cambridgeshire or Fenland, UK. The goal of the Fenland Study is to study the interactions between diet, lifestyle, and genetic factors and risk of diabetes and obesity. A total of 1,401 individuals with genotype data and lipid measurements were included in the current analysis.Back to top
InCHIANTI62 is an epidemiological study of risk factors contributing to the decline in physical functioning in late life. Individuals were selected from the population registries of two small towns in Tuscany, Italy. Participants, all of white European origin, were invited to a clinic visit for evaluation of health status as described in detail previously63. Genotype data and lipid measurements were available for 1,134 individuals.
62. Ferucci, L. et al. Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study. J. Am. Geriatr. Soc. 48, 1618-1625 (2000).
63. Bartali, B. et al. Changes in anthropometric measures in men and women across the lifespan: findings from the InCHIANTI study. Soz. Praventivmed. 47, 336-348 (2002).Back to top
LOLIPOP is an ongoing community cohort of approximately 30,000 individuals aged 35-75 years, recruited in West London, UK64 to study the environmental and genetic factors that contribute to cardiovascular disease among UK Indian Asians. The study includes both European and Indian Asian subjects. Indian Asian participants reported having all four grandparents born on the Indian subcontinent, while European participants are self-classified whites born in Europe. For the current study, genotypes and lipid measurements were available for 1,599 European white individuals included in the primary meta-analysis.
64. Chambers, J.C. et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat. Genet. 40, 716-718 (2008).Back to top
The FINRISK study is a population survey of risk factors for chronic, non-communicable diseases carried out in Finland. Since 1972, the survey has been performed every five years using independent, random and representative population samples from different parts of the country65. Participants complete a questionnaire and undergo a physical examination, including measurement of anthropometric traits and blood draw. The current analysis included 910 healthy individuals from the Helsinki area, who participated in a FINRISK survey and had genotype data and lipid measurements available.
65. Vartiainen, E. et al. Thirty-five-year trends in cardiovascular risk factors in Finland. Int. J. Epidemiol. 39, 504-518 (2010).Back to top
The NFBC1966 has been described in paper66. The study was originally designed to study factors affecting pre-term birth, low birth weight, and subsequent morbidity and mortality. Mothers living in the two northern-most provinces of Finland were invited to participate if they had expected delivery dates during 1966. A total of 12,058 live-births were included in the study. At age 31, 5,923 individuals still living in the Helsinki area or Northern Finland were asked to participate in a detailed biological and medical examination as well as a questionnaire. Genotypes and lipid measurements were available for 5,138 individuals included in this analysis.
66. Rantakallio, P. Groups at risk in low birth weight infants and perinatal mortality. Acta Paed Scand. 193 Suppl 193, 1-71 (1969).Back to top
Rotterdam Study is an ongoing prospective population-based cohort study, focused on chronic disabling conditions of the elderly. The study comprises an outbred ethnically homogenous population of Dutch Caucasian origin. The rationale of the study has been described in detail elsewhere67,68. In summary, 7,983 men and women aged 55 years or older, living in Ommoord, a suburb of Rotterdam, the Netherlands, were invited to participate. A total of 5,701 individuals from the initial study were included in the current study. In 20002001, a second cohort was established with approximately 3,000 individuals, 1,628 of whom were included in this study.
67. Hofman, A., Grobbee, D.E., de Jong, P.T., & van den Ouweland, F.A. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur. J. Epidemiol. 7, 403-22 (1991).
68. Hofman, A. et al. The Rotterdam Study: objectives and design update. Eur. J. Epidemiol. 22, 819-829 (2007).Back to top
The SUVIMAX study has been described in papers. SUVIMAX was a controlled randomized primary prevention trial to study the effects of supplemented vitamins and minerals on cardiovascular disease and cancers in French men and women between 45-60 and 35-60 years of age, respectively. A total of 1,813 individuals with lipid measurements were included in the current analysis.
69. Hercberg, S. et al. A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study--design, methods, and participant characteristics. SUpplementation en VItamines et Minéux AntioXydants. Control Clin. Trials. 19, 336-351 (1998).
70. Hercberg, S. et al. Background and rationale behind the SU.VI.MAX Study, a prevention trial using nutritional doses of a combination of antioxidant vitamins and minerals to reduce cardiovascular diseases and cancers. SUpplementation en VItamines et Minéux AntioXydants Study. Int. J. Vitam. Nutr. Res. 68, 3-20 (1998).Back to top
The WGHS has been described in paper71. Participants were drawn from the Women's Health Study, where they had been followed over a 12-year period and monitored for serious healthrelated events, including myocardial infarction, stroke, and diabetes. Genomewide genotyping was performed on individuals within the WGHS, and 22,041 participants with lipid measurements were included in the current analysis.
71. Ridker, P.M. et al. Rationale, design, and methodology of the Womens Genome Health Study: a genome-wide association study of more than 25,000 initially healthy American women. Clin. Chem. 54, 249-55 (2008).Back to top
The BRIGHT study has been described in paper72. Individuals diagnosed with hypertension before age 60 were recruited to study hypertension, an important risk factor for coronary artery and cerebrovascular diseases. All individuals reported having four grandparents of white British ancestry. A total of 1,615 hypertensive cases with lipid measurements were included in the current analysis.
72. Caulfield, M. et al. Genome-wide mapping of human loci for essential hypertension. Lancet. 361, 2118-2123 (2003).Back to top
The B58C-T1DGC is a sample from the national population-based 1958 Birth Cohort collected in the UK and sampled periodically from birth to age 44-45 years73. Samples are distinct from those included in the B58C-WTCCC cohort described above. A total of 2,534 individuals with lipids measurements were included in the current analysis.
73. Barrett, J.C. & et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703-707 (2009).Back to top
The DGI study has been described in papers74,75. The DGI study is a type 2 diabetes case-control study that includes 1,588 T2D cases and 1,523 matched controls of European ancestry from Sweden and Finland. A total of 1,528 cases and 1,508 controls with lipid measurements were included in the current analysis.
74. Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 316, 1331-1336 (2007).
75. Groop, L. et al. Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes. 45, 1585-93 (1996).Back to top
The EPIC-Norfolk study76,77 is an ongoing prospective cohort study of chronic diseases comprising 25,663 Norfolk residents, an ethnically homogenous European origin population aged 39-79 years who were recruited from general practice registers between 1993 and 1997 for a first health examination. A subcohort of 1,078 obese (BMI ≥ 30 kg·m-2) individuals with lipid measurements was included in the current analysis.
76. Day, N. et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br. J. Cancer. 80, 95-103 (1999).
77. Harding, A.H. et al. Dietary fat and the risk of clinical type 2 diabetes: the European Prospective Investigation of Cancer-Norfolk study. Am. J. Epidemiol. 159, 73-82 (2004).Back to top
The FHS is a multicenter study of the genetic and non-genetic risk factors for coronary heart disease and has been described in paper78. A total of 356 individuals with coronary heart disease and 394 controls with lipid measurements were available for the current analysis.
78. Arnett, D.K. et al. Angiotensinogen and angiotensin converting enzyme genotypes and carotid atherosclerosis: the Atherosclerosis Risk in Communities and the NHLBI Family Heart Studies. Atherosclerosis. 138, 111-116 (1998).Back to top
The FUSION study has been described in papers79,80. The FUSION GWAS is a type 2 diabetes (T2D) case-control study that includes 1,161 Finnish T2D cases and 1,174 normal glucose tolerant (NGT) controls. A total of 772 cases and 982 controls with lipid measurements were included in the current analysis.
79. Valle, T. et al. Mapping genes for NIDDM. Design of the Finland-United States Investigation of NIDDM Genetics (FUSION) Study. Diabetes Care. 21, 949-958 (1998).
80. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 316, 1341-1345 (2007).Back to top
The GenMets sample has been described in paper81. Individuals are metabolic syndrome cases and matched controls drawn from the Finnish Health2000 study. A total of 867 metabolic syndrome cases and 892 controls with genotype data and lipid measurements were included in the current analysis.
81. Perttilä J. et al. OSBPL10, a novel candidate gene for high triglyceride trait in dyslipidemic Finnish subjects, regulates cellular lipid metabolism. J. Mol. Med. 87, 825-835 (2009).Back to top
MedSTAR is a cross-sectional study of coronary atherosclerosis that has been described in paper82. 1,500 subjects who underwent cardiac catheterization at the Washington Hospital Center between August 2004 and March 2007 were recruited to participate. The cohort is comprised of 874 cases with history of coronary artery disease (CAD) and 447 controls without history of CAD. A total of 716 CAD cases and 393 controls with genotype data and lipid measurements were included in the present study.
82. Myocardial Infarction Genetics Consortium et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334-341 (2009).Back to top
PennCATH is an angiographic study based at the University of Pennsylvania Medical Center that has been described in paper83. Individuals who underwent cardiac catheterization at Penn between July 1998 and March 2003 were invited to participate. The cohort is comprised of 933 CAD cases and 468 controls with no history of CAD. The current analysis included 892 CAD cases and 454 controls with genotype data and lipid measurements available.
83. Lehrke, M. et al. CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humans. J. Am. Coll. Cardiol. 49, 442-449 (2007).Back to top
The ERF study has been described in paper84. A total of approximately 3,000 participants descend from 22 couples who lived in the Rucphen region in The Netherlands in the 19th century. A total of 1,108 individuals with genotype data and lipid measurements were included in the current analysis.
84. Pardo, L.M., MacKay, I., Oostra, B., van Duijn, C.M. & Aulchenko, Y.S. The effect of genetic drift in a young genetically isolated population. Ann. Hum. Genet. 69, 288-295 (2005).Back to top
The FramHS is a three generational prospective cohort that has been described in paper85. Individuals were initially recruited in 1948 in Framingham, USA to evaluate cardiovascular disease risk factors. The second generation cohort (5,124 offspring of the original cohort) was recruited between 1971 and 1975, and multiple lipid measurements were available and have been averaged. The third generation cohort (4,095 grand-children of the original cohort) was collected between 2002 and 2005, and a single lipid measurement was available. The current analysis includes 7,132 individuals for whom genotypes and lipid measurements were available.
85. Kannel, W.B. et al. III. Factors of risk in the development of coronary heart diseasesix year follow-up experience. The Framingham Study. Ann. Intern. Med. 55, 33-50 (1961).Back to top
The MICROS study has been described in paper86. As part of the genomic healthcare program "GenNova," an extensive survey was carried out during 2001-2003 in three villages of the Val Venosta (South Tyrol, Italy) on the populations of Stelvio, Vallelunga, and Martello. The current analysis includes 1,037 individuals for whom genotype data and lipid measurements were available.
86. Pattaro, C. et al. The genetic study of three population microisolates in South Tyrol (MICROS): study design and epidemiological perspectives. BMC Med. Genet. 8, 29 (2007).Back to top
The NSPHS is a familybased prospective population study in Sweden. The parish of Karesuando, in the subartic region of the County of Norrbotten, has about 1,500 inhabitants, 740 of whom participated in the study. The region has experienced little immigration during the last 200 years. The current analysis included 593 individuals for whom genotypes and lipid measurements were available.Back to top
ORCADES is an ongoing family-based genetic epidemiology collection in the isolated Scottish archipelago of Orkney. The current analysis included 633 individuals from a subgroup of the Orkney islands who had genotype data and lipid measurements available for study.Back to top
The SardiNIA study has been described in paper87. The study includes 4,301 related individuals from the Ogliastra region of Sardinia, Italy who have been studied longitudinally for age-related quantitative traits. The current study included 4,184 individuals with genotype data and lipid measurements available.
87. Pilia, G. et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet. 2, e132 (2006).Back to top
The Vis study has been described in paper88. Croatians aged 18-93 years were recruited from the villages of Vis and Komiza on the Dalmation island of Vis between 2003 and 2004. The current analysis included 771 individuals for whom genotype data and lipid measurements were available.
88. Rudan, I., Campbell, H. & Rudan, P. Genetic epidemiological studies of eastern Adriatic Island isolates, Croatia: objective and strategies. Coll. Antropol. 23, 531-546 (1999).Back to top
The Malmö and Cancer Study, a community-based prospective epidemiologic cohort of 28,449 persons recruited for a baseline examination between 1991 and 199689. From this cohort, 6,103 persons were randomly selected to participate in the cardiovascular cohort, which sought to investigate risk factors for cardiovascular disease. All participants underwent a medical history assessment and a physical examination. Of the participants in the cardiovascular cohort, 4,991 had DNA samples available for this analysis and data available for at least one lipoprotein or lipid phenotype.
89. Berglund, G., Elmstahl, S., Janzon, L. & Larsson, S.A. The Malmo Diet and Cancer Study. Design and feasibility. J. Intern. Med. 233, 45-51 (1993).Back to top
FINRISK97 was a population-based cross-sectional survey designed to study the prevalence of cardiovascular risk factors in Finland90. Surveys are conducted every 5 years, and the 1997 survey included 8,389 Finnish men and women aged 25-74. Participants underwent a physical examination and completed a questionnaire regarding cardiovascular risk factors. Of these FINRISK97 participants, 7,026 had DNA samples available for this analysis and data available for at least one lipoprotein or lipid phenotype.
90. Vartiainen, E. et al. Cardiovascular risk factor changes in Finland, 1972-1997. Int. J. Epidemiol. 29, 49-56 (2000).Back to top
CARDIoGRAM combines data from all published and several unpublished GWAS including individuals with European ancestry, includes > 22,000 cases with CAD and/or MI and > 60,000 controls, and unifies samples from Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium91. CAD was defined as: 1) coronary artery stenosis > 50% in at least one major epicardial artery; 2) fatal MI; 3) non-fatal MI based on ECG and cardiac biomarkers; 4) angina with positive stress testing; 5) percutaneous transluminal angioplasty; or 6) coronary artery bypass surgery. The control definition varied by study and ranged from population-based controls to selfreported freedom from CAD to lack of obstructive lesions on coronary angiography. Genotyping platforms and quality control criteria have been described91.
91. Preuss, M. et al. Design of the Coronary ARtery DIsease Genome-wide Replication And Meta-Analysis (CARDIoGRAM) Study-a genome-wide association meta-analysis involving more than 22,000 cases and 60,000 controls. Submitted.Back to top
The COROGENE study includes individuals who underwent coronary angiography in Helsinki University Hospital, Finland and matched controls. Cases (n = 2,172) were individuals admitted to the Helsinki University Hospital for acute coronary syndrome (unstable angina pectoris or acute myocardial infarction). Controls (n = 1,579) were age- and sex- and area of residence matched individuals from the FINRISK 1997, 2002, or 2007 studies. Genotype and quality control criteria have been described92.
92. Soranzo, N. et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat. Genet. 41, 1182-1190 (2009).Back to top
For the study of the cumulative effects of common variants in individuals at the extremes of the HDL distribution, cases with high HDL (> 90th percentile for age, gender, and race) were selected from the University of Pennsylvania High HDL Cholesterol Study (HHDL) and controls with low HDL (< 30th percentile for age, gender, and race) were selected from the University of Pennsylvania Catheterization cohort (PennCATH). HHDL is a cross-sectional study of genetic factors contributing to elevated HDL-C levels. Probands with elevated HDL-C (> 75th percentile for age and gender) were identified by physician referrals or through the Hospital of the University of Pennsylvania clinical laboratory93. Relatives of HHDL probands were also invited to participate in the study. Subjects completed a lifestyle questionnaire and provided a blood sample for the measurement of HDL and other lipid-related traits. Genotyping was performed at the Center for Applied Genomics (Children's Hospital of Pennsylvania) following manufacturer specifications for amplification and hybridization to the Affymetrix Genome-Wide Human SNP Array 6.0. Quality control measures to exclude unreliable SNPs and eliminate SNPs with genotype call rate < 95%, with minor allele frequency (MAF) < 1% or if there was significant departure from Hardy-Weinberg equilibrium (P < 1 x 10-6 in combined cases and controls) were performed. Imputation was conducted using a Hidden Markov Model algorithm as implemented in MACH.
93. Lehrke, M. et al. CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humans. J. Am. Coll. Cardiol. 49, 442-449 (2007).Back to top
Blood samples of unrelated hypercholesterolemic patients were collected from 64 Dutch Lipid Clinics. Based on clinical criteria, all patients were suspected for familial hypercholesterolemia by cardiologists and internists using a uniform protocol and internationally accepted criteria94,95. All patients were routinely analysed for the presence of mutations by direct sequencing of the complete LDLR and the LDL-receptor binding region of APOB (amino acids 3414 to 3588). For the identification of large rearrangements in the LDLR gene, a multiplex ligation-dependent probe (MLPA) technique with the Salsa P062 LDLR Exon Deletion Test Kit (MRC-Holland, Amsterdam, the Netherlands) was used, according to the manufacturer's instructions. For this analysis, we considered only the 344 patients in whom a functional LDLR or APOB mutation was not identified. After an overnight fast, blood was sampled, and plasma concentrations of total cholesterol, HDL-C, and triglycerides were measured by commercially available kits (Boehringer Mannheim, Mannheim, Germany). LDL-C concentrations were calculated by the Friedewald formula only when the triglyceride concentration was below 4.5 mmol/L. Genomic DNA was prepared from 10 ml whole blood on an AutopureLS apparatus according to a protocol provided by the manufacturer (Gentra Systems, Minneapolis, MI, USA).
94. Defesche, J.C. Familial hypercholesterolemia. In: Betteridge, D.J., ed. Lipids and Vascular Disease: Current Issues. London: Martin Dunitz, 65-76 (2000).
95. Goldstein, J.L., Hobbs, H.H. & Brown, M.S. Familial hypercholesterolemia. In: Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D., eds. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill, 1981-2030 (1995).Back to top
In total, 344 unrelated adult subjects of European ancestry with hypertriglyceridemia, defined as having untreated 12 h fasting plasma triglyceride concentrations > 3 mmol/L on at least two occasions, were studied96. Patients were ascertained through a single tertiary referral lipid clinic, and had undergone complete medical history and examination, together with collection of demographic, clinical, and biochemical variables. Low triglyceride control subjects were comprised of 144 unrelated adult subjects of European ancestry with fasting plasma triglyceride concentrations < 2.4 mmol/L, including both healthy population-based controls from Ontario and subjects with molecularly confirmed familial hypercholesterolemia. Study subjects were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0 platform (Affymetrix, Santa Clara, CA), according to protocols of the London Regional Genomics Centre (www.lrgc.ca). Genotypes were called using Affymetrix Genotyping Console, setting quality control thresholds for SNP call rate (95%), Hardy-Weinberg equilibrium (P > 0.0001) and minor allele frequency (>1%). SNP imputation was subsequently conducted using phased haplotypes from the European HapMap cohort in MACH.
96. Hegele, R.A. et al. A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Hum. Mol. Genet. 18, 4189-4194 (2009).Back to top
Samples for analysis were from the Cholesterol and Atherosclerosis Pharmacogenetics (CAP) Study49. CAP was a clinical trial designed to identify genetic influences responsible for inter-individual variation in response to simvastatin. CAP participants were 944 Caucasiansand African Americans, aged 30 and above, who received open label 40 mg simvastatin daily for 6 weeks. They were recruited on the basis of having serum total cholesterol levels of 4.14-10.36 mmol/L (160-400 mg/dL). Complete phenotypes of lipids before and after statin treatment and Metabochip data are available on 530 Caucasian CAP participants.
49. Simon, J.A. et al. Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am J Cardiol97, 843-50 (2006).Back to top
MORGAM is a multinational collaborative study exploring the relationships between the development of cardiovascular diseases, their classic and genetic risk factors and biomarkers50.
50. Evans, A. et al. MORGAM (an international pooling of cardiovascular cohorts). Int J Epidemiol34, 21-7 (2005).Back to top
When using downloaded data, please cite the corresponding paper:
Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 45, 1274-83 (2013).
Teslovich TM et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707-13 (2010).
Kathiresan S et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 41, 56-65 (2009).
Willer CJ et al. Newly identified loci that influence lipid concentrations and riskof coronary artery disease. Nat Genet. 40, 161-9 (2008).
Kathiresan S et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 40, 1 89-97 (2008).
Ongoing GLGC projects include:
Exome array of > 300,000 individuals elucidates contribution of protein altering variation in plasma lipid levels. Dajiang Liu et al
Create regional association plots of GWAS results using LocusZoom:
Pruim RJ*, Welch RP*, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abeca sis GR, Willer CJ. LocusZoom: Regional visualization of genome-wide association scan resul ts. Bioinformatics 26, 2336-2337 (2010).