To access publisher's full text version of this article click on the hyperlink below ; OBJECTIVE: To study the association of fish and fish-liver oil consumption across the lifespan with CHD later in life among Icelandic women, with special emphasis on the effects of consumption in adolescence. DESIGN: Prevalence association study. Logistic regression was used to estimate odds ratios and 95 % confidence intervals of CHD according to fish or fish-liver oil exposure. Models were adjusted for age, education, concurrent diet and other known risk factors. SETTING: The study was nested within the AGES-Reykjavik Study, conducted in Reykjavik, Iceland. SUBJECTS: Participants were 3326 women aged 66-96 years, with available information on CHD status at entry to the study and information on fish and fish-liver oil consumption during midlife and adolescence. Dietary habits were assessed retrospectively using a validated FFQ. RESULTS: CHD was identified in 234 (7·9 %) women. Compared with women with no intake of fish-liver oil in adolescence or midlife, women who consumed fish-liver oil at least three times weekly in adolescence or in midlife had a decreased risk of CHD (OR=0·62; 95 % CI 0·45, 0·85 and OR=0·68; 95 % CI 0·50, 0·94, respectively). No associations were observed between fish intake (>2 portions/week v. ≤2 portions/week) in adolescence or midlife and CHD in this population with high fish intake. CONCLUSIONS: Fish-liver oil consumption, from early life, may reduce the risk of CHD in older women. Lifelong nutrition may be of importance in the prevention of CHD in older women. ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA) Icelandic Heart Association Icelandic Parliament United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA) Icelandic Parlament
To access publisher's full text version of this article click on the hyperlink at the bottom of the page ; There is little evidence on the long-term association between physical activity (PA) and depressive symptoms in old age. We examined the association of midlife PA and depressive symptoms in late life. ; A large community-based population residing in Reykjavik, Iceland, participated in a longitudinal study with an average of 25 years of follow up. Midlife PA was categorized as active and inactive groups (n = 4,140, Active = 1,292, Inactive = 2,848, mean age 52±7 years). The main outcome had six or higher depressive symptoms assessed by the 15-item Geriatric Depression scale. Participants who had a history of depression (n = 226), and were diagnosed with dementia (n = 393), and had incomplete cognitive data (n = 595) and incomplete analytical data (n = 422) were excluded. Level of weekly PA was ascertained by a questionnaire at midlife. Depressive symptoms were assessed on average 25 (±4) years later. ; After controlling for demographic and health-related risk factors, those who were active at midlife were less likely to have high level of depressive symptomatology (6 or higher Geriatric Depression scale scores, odds ratio = 0.58, 95% confidence interval: 0.41-0.83, p < .005) compared with those who were inactive in midlife. After full adjustment of three domains of late-life cognitive function the results remained significant (odds ratio = 0.61, 95% confidence interval: 0.43-0.86, p = .005). ; Our study shows that midlife PA is associated with lower depressive symptoms 25 years later. Participating in regular PA in midlife may improve mental health in late life. ; National Institutes of Health/N01-AG-12100 National Institute on Aging Intramural Research Program Icelandic Heart Association Landspitali University Hospital Icelandic Parliament
Publisher's version (útgefin grein) ; Recent studies indicate that lifestyle factors in early life affect breast cancer risk. We therefore explored the association of high consumption of meat, milk, and whole grain products in adolescence and midlife, on breast cancer risk. We used data from the population based AGES-Reykjavik cohort (2002–2006), where 3,326 women with a mean age of 77 years (SD 6.0) participated. For food items and principal component derived dietary patterns we used Cox proportional models to calculate multivariate hazard ratios (HR) with 95% confidence intervals (95% CI). During a mean follow-up of 8.8 years, 97 women were diagnosed with breast cancer. For both adolescence and midlife, daily consumption of rye bread was positively associated with breast cancer (HR 1.7, 95% CI 1.1–2.6 and HR 1.8, 95% CI 1.1–2.9, respectively). In contrast, persistent high consumption of oatmeal was negatively associated with breast cancer (0.4, 95% CI 0.2–0.9). No association was found for other food items or dietary patterns that included rye bread. High rye bread consumption in adolescence and midlife may increase risk of late-life breast cancer whilst persistent consumption of oatmeal may reduce the risk. ; The AGES-Reykjavik Study was funded by NIH contract N01-AG-12100, the Intramural Research Program of the National Institute on Aging, by the Icelandic Heart Association and the Icelandic Parliament. This work was supported by the The Icelandic Centre for Research, RANNIS grant number: 152495051, (http://en.rannis.is/) (A. Haraldsdottir) and the Public Health Fund of the Icelandic Directorate of Health (A. Haraldsdottir). The funding agencies (National Institute on Aging, Icelandic Heart Association and Icelandic Parlament,) for the AGES-Reykjavik Study, RANNIS, or Directorate of Health had no role in the design, analysis or writing of this article. ; Peer Reviewed
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. ; The aim of this study was to investigate the associations between loss of a life partner and the development of dementia and decline in cognitive function in later life. We used an Icelandic cohort of 4,370 participants in the Age, Gene/Environment Susceptibility-Reykjavik Study who were living as married in 1978 (born in 1907-1935) and were either still married (unexposed cohort) or widowed (exposed cohort) at follow-up (in 2002-2006). We ascertained history of marital status and spouse's death by record linkage to the Registry of the Total Population, Statistics Iceland. The outcome measures were as follows: 1) dementia and mild cognitive impairment; and 2) memory, speed of processing, and executive function. During the observation period, 3,007 individuals remained married and 1,363 lost a spouse through death. We did not find any significant associations between loss of a spouse and our outcome variables, except that widowed women had poorer executive function (mean = -0.08) during the first 2 years after their husbands' deaths compared with still-married women (mean = 0.09). Our findings do not support the notion that the risk of dementia is increased following the loss of a spouse, yet women demonstrate a seemingly temporary decline in executive function following the death of a partner. ; University of Iceland Research Fund for Graduate Students Icelandic Research Fund for Graduate Students (Rannis) Memorial Fund of Helga Jonsdottir and Sigurlidi Kristjansson Research Fund of Oldrunarrad Islands Icelandic Gerontological Society Research Fund Fund of Gudmundur Andresson Swedish Society for Medical Research National Institute on Aging N01-AG-1-2100 National Institute on Aging Icelandic Parliament Icelandic Heart Association
Publisher's version (útgefin grein) ; Background: Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. Methods: In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Results: Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. Conclusion: Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy. ; This work was supported by National Institutes of Health grants R01 AG027012 and R01 EY017362, the Intramural Research Programs of the National Institute on Aging and the National Eye Institute (ZIAEY00401 and National Institutes of Health contract numbers N01-AG-1-2100 and HHSN271201200022C), the Iceland Heart Association, the Icelandic Parliament, and the University of Iceland Research Fund. The National Eye Institute was involved in the design and conduct of the study in regard to collection of fundus photographs. The funders had no role in data collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. ; Peer Reviewed
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download ; Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy. ; National Institutes of Health National Institute on Aging National Eye Institute Iceland Heart Association Icelandic Parliament University of Iceland Research Fund
Publisher's version (útgefin grein) ; The etiology of monoclonal gammopathy of undetermined significance (MGUS), the precursor state of multiple myeloma (MM), is mostly unknown and no studies have been conducted on the effect of diet on MGUS or progression from MGUS to MM. We aimed to explore the association between common foods and MGUS and progression to MM. Data from the population-based AGES Study (N = 5,764) were utilized. Food frequency questionnaire was used to assess dietary intake during adolescence, midlife, and late life. Serum protein electrophoresis and serum free light-chain assay was performed to identify MGUS (n = 300) and LC-MGUS cases (n = 275). We cross linked our data with the Icelandic Cancer Registry to find cases of MM in the study group. We found that intake of fruit at least three times per week during adolescence was associated with lower risk of MGUS when compared to lower fruit consumption (OR = 0.62, 95% CI 0.41–0.95). We additionally found that intake of fruit at least three times per week during the late life period was associated with decreased risk of progressing from MGUS to MM (HR = 0.34, 95% CI 0.13–0.89) when compared to lower intake. Adolescent intake of fruit may reduce risk of MGUS, whereas fruit intake after MGUS onset may reduce risk of progressing to MM. Our findings suggest that diet might alter the risk of developing MGUS and progression to MM. ; The AGES-Reykjavik Study was funded by NIH contract N01-AG-012100, the Intramural Research Program of the National Institute on Aging, by the Icelandic Heart Association, and the Icelandic Parliament. This work was supported by the Icelandic Centre for Research, RANNIS (S.Y. Kristinsson), the Landspitali University Hospital Research Fund (S.Y. Kristinsson), the Karolinska Instituted Foundations (S.Y. Kristinsson), the Marie Curie CIG (S.Y. Kristinsson), and the Memorial Sloan Kettering Core Grant (P30 CA008748) from the National Cancer Institute (O.Landgren). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer Reviewed
Article in press ; Dynamic sitting, such as fidgeting and desk work, might be associated with health, but remains difficult toidentify out of accelerometry data. We examined, in a laboratory study, whether dynamic sitting can beidentified out of triaxial activity counts. Among 18 participants (56% men, 27.3 ± 6.5 years), up to 236 countsper minute were recorded in the anteroposterior and mediolateral axes during dynamic sitting using a hip-worn accelerometer. Subsequently, we examined in 621 participants (38% men, 80.0 ± 4.7 years) from theAGES-Reykjavik Study whether dynamic sitting was associated with cardio-metabolic health. Compared toparticipants who recorded the fewest dynamic sitting minutes (Q1), those with more dynamic sittingminutes had a lower BMI (Q2=−1.39 (95%CI =−2.33;–0.46); Q3=−1.87 (−2.82;–0.92); Q4=−3.38 (−4.32;–2.45)), a smaller waist circumference (Q2=−2.95 (−5.44;–0.46); Q3=−3.47 (−6.01;–0.93); Q4=−8.21 (−10.72;–5.71)), and a lower odds for the metabolic syndrome (Q2= 0.74 [0.45;1.20] Q3= 0.58 [0.36;0.95]; Q4=0.36[0.22;0.59]). Our findings suggest that dynamic sitting might be identified using accelerometry and that thisbehaviour was associated with health. This might be important given the large amounts of time peoplespend sitting. Future studies with a focus on validation, causation and physiological pathways are needed tofurther examine the possible relevance of dynamic sitting. ; This work was supported by the National Institute on Aging;National Institutes of Health [N01-AG-12100];FP7 People: Marie-Curie Actions (FP7- PEOPLE-2011-CIG) [PCIG09-GA-2011-293621];Icelandic Heart Association; Icelandic Parliament. ; Peer reviewed
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download ; Dynamic sitting, such as fidgeting and desk work, might be associated with health, but remains difficult to identify out of accelerometry data. We examined, in a laboratory study, whether dynamic sitting can be identified out of triaxial activity counts. Among 18 participants (56% men, 27.3 ± 6.5 years), up to 236 counts per minute were recorded in the anteroposterior and mediolateral axes during dynamic sitting using a hip-worn accelerometer. Subsequently, we examined in 621 participants (38% men, 80.0 ± 4.7 years) from the AGES-Reykjavik Study whether dynamic sitting was associated with cardio-metabolic health. Compared to participants who recorded the fewest dynamic sitting minutes (Q1), those with more dynamic sitting minutes had a lower BMI (Q2 = -1.39 (95%CI = -2.33;-0.46); Q3 = -1.87 (-2.82;-0.92); Q4 = -3.38 (-4.32;-2.45)), a smaller waist circumference (Q2 = -2.95 (-5.44;-0.46); Q3 = -3.47 (-6.01;-0.93); Q4 = -8.21 (-10.72;-5.71)), and a lower odds for the metabolic syndrome (Q2 = 0.74 [0.45;1.20] Q3 = 0.58 [0.36;0.95]; Q4 = 0.36 [0.22;0.59]). Our findings suggest that dynamic sitting might be identified using accelerometry and that this behaviour was associated with health. This might be important given the large amounts of time people spend sitting. Future studies with a focus on validation, causation and physiological pathways are needed to further examine the possible relevance of dynamic sitting. ; National Institute on Aging National Institutes of Health FP7 People: Marie-Curie Actions (FP7-PEOPLE-2011-CIG) Icelandic Heart Association Icelandic Parliament
Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant.
Abstract Background Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. Methods We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. Results Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1 ) in EA .
Abstract Background Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. Methods We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. Results Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region. Conclusions While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.
CONTEXT: Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. OBJECTIVE: The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. DESIGN: Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). PATIENTS OR OTHER PARTICIPANTS: In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. MAIN OUTCOME MEASURES: Blood concentrations of 25(OH)D were measured for all participants. RESULTS: Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. CONCLUSIONS: Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.
Publisher's version (útgefin grein) ; Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D. ; WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The grant funding of WHI are R21 HL123677, R56 DK104806 and R01 MD012765 to NF. The FamHS was funded by R01HL118305 and R01HL117078 NHLBI grants, and 5R01DK07568102 and 5R01DK089256 NIDDK grant." and "The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (project # Z01-AG000513 and human subjects protocol number 09-AGN248). Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL119443, HL087660, HL054464, HL054457, and HL054481) of the National Institutes of Health. Ruth loos is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). The Rotterdam Study GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006- 01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002- 01254). The ERF study was further supported by ENGAGE consortium and CMSB. Highthroughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWORFBR 047.017.043).ERF was further supported by the ZonMw grant (project 91111025), and this work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6- 4278). This study is also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to Drs. Meigs, Dupuis and Florez, NIDDK K24 DK080140 to Dr. Meigs, and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr. Florez. The HERITAGE Family Study was supported by National Heart, Lung, and Blood Institute grant HL-45670. The Women's Genome Health Study is supported by the National Heart, Lung, and Blood Instutute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913). Additional support for endpoint collection was provided by the National Heart, Lung, and Blood Institute under ARRA funding (HL099355). HyperGEN (Hypertension Genetic Epidemiology Network): The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673- 12. The AGES study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease)"and "Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6, the Scottish Funding Council HR03006 and the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z) for Stratifying Resilience and Depression Longitudinally (STRADL). Genotyping was funded by the UK's Medical Research Council. Jose C. Florez, NIDDK K24 DK110550 The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Additionally, one or more authors are affiliated with the following commercial entities: Interleukin Genetics, GlaxoSmithKline, Daiichi-Sankyo, AstraZeneca, Data Tecnica International LLC, Illumina Inc., University of California Healthcare, Janssen Pharmaceuticals, Goldfinch Bio, and Novo Nordisk. Please see the Competing Interests Statement for additional details. The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. ; Peer Reviewed