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MESA Genetics and MESA SHARe P&P Activities

MESA Genetics and MESA SHARe P&P Activities. September 21, 2011 Jerome I. Rotter. MESA SHARe Phenotype Working Groups. 20 MESA SHARe Phenotype Working Groups actively meet.

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MESA Genetics and MESA SHARe P&P Activities

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  1. MESA Genetics and MESA SHARe P&P Activities September 21, 2011 Jerome I. Rotter

  2. MESA SHARe Phenotype Working Groups • 20 MESA SHARe Phenotype Working Groups actively meet. • Since April 2010, 75 publication proposals, and 16pen drafts were submitted from 17 different Phenotype Working Groups and SHARe Committees • 19proposals use standard analysis plan developed by MESA SHARe Analysis Committee, 52 follow analysis outlined by consortia, and 4 use non-standard analysis as defined by the Working Group • 7 published papers • Includes collaborations with CHARGE, ICBP, MACAD, PRIMA, GENEVA, CARe, NOMAS, Type 2 DM Consortium, CARDIA, SPIROMETA, HealthABC, SUNLIGHT, CKDGen, FIND, WHI, Family Heart Study, Genestar, Diabetic Heart Study, Framingham, AGES

  3. MESA SHARe Phenotype Working Groups

  4. MESA SHARe Published Papers

  5. MESA SHARe Published Papers

  6. MESA SHARe Pen Drafts

  7. MESA Genetics Overview There are now 7 updates of MESA SHARe phenotypes, and we have added the Care IBC candidate gene data as well. MESA SHARe Newsletter was distributed to participants We have now expanded to 13 MESA SHARe analytic sites The third in-person MESA SHARe meeting was held on 2/9/11 in Boston, preceding the meeting of the CHARGE (Cohorts for Heart and Aging Research in Genetic Epidemiology consortium). The focus was on the “Multi-ethnic in MESA.” 151 MESA Genetics proposals have submitted with 21 papers published, and 17 pen drafts submitted.

  8. CRTC3 Links Catecholamine Signaling to Energy Balance.Song Y, Altarejos J, Goodarzi MO, …, Guo X, …, Chen YDI, Taylor KD,…, Rotter JI, Montminy M. Nature. 468:933-939 (2010). • CRTC3 knockout mice are protected against diet-induced obesity • S72N is a common human variant. 72N found to have increased CRTC3 activity in vitro. • MACAD: 72N associated with increased weight, increased BMI, and increased hip circumference • MESA Hispanics: 72N associated with increased BSA and a trend to increased weight • Association not observed in non-Hispanic whites: MESA, CHARGE, GIANT • 72N is minor allele in Hispanics, major allele in non-Hispanic whites High fat diet Fat mass on high fat diet

  9. Genetic variants in novel pathways influence blood pressure and cardiovascular disease riskThe International Consortium for Blood Pressure Genome-Wide Association Studies. Ehret G et al., Nature (Published online September 11, 2011; MESA authors: Palmas, Raffel, Yao, Guo) • Genome-wide association meta-analysis, n=200,000 Caucasians. • Twenty-nine independent SNPs at 28 loci were significantly associated with SBP, DBP, or both (all p<5E-09). • Of them, 16 loci were novel; 6 contain genes previously known or suspected to regulate blood pressure (GUCY1A3–GUCY1B3, NPR3–C5orf23, ADM, FURIN–FES, GOSR2, GNAS–EDN3); the other 10 may provide new clues to blood pressure physiology. • A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease. That score was also associated with BP levels in East Asian, South Asian, and African ancestry populations.

  10. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressureThe International Consortium for Blood Pressure Genome-Wide Association Studies. Wain L et al., Nature Genetics (Published online September 11, 2011; MESA authors: Palmas, Chen, Burke, Guo) • Genome-wide (GW) association meta-analysis of pulse pressure (PP) and mean arterial pressure (MAP). • In discovery (N = 74,064) and follow-up studies (N = 48,607) GW significance was reached for 7 new loci: 4 new PP loci (at 4q12 near CHIC2, 7q22.3near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), 2 new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and 1 locus associated with both traits(2q24.3 near FIGN). • For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects. • These findings may help identify novel biological mechanisms of hypertension. PP MAP

  11. Genetic Loci Associated with Plasma Phospholipid n-3 Fatty Acids: A Meta-Analysis of Genome-wide Association Studies from the CHARGE ConsortiumLemaitre, Tanaka, Tang, Manichaikul, Foy et al PLoSGenet. 2011 Jul;7:e1002193. • ALA, EPA, DHA, DPA • Meta-analysis of GWAS in MESA, CHS, ARIC, CARDIA, InCHIANTI • 8,866 subjects, European descent • TOP FIGURE: Metabolic genes logically associated with each n-3 PUFA • DPA associated with GCKR (not shown) • Similarities /diff in other ethnicities (other paper lead by Ani) • BOTTOM FIGURE: Weaker association of ALA (precursor) with EPA (product) in carriers of FADS variants • Implies more benefit of plant n-3 consumption (eg canola oil) in carriers of major allele.

  12. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Soler Artigas M, …, Manichaikul A, …, Liu Y, …, Barr RG, …, Rich SS, …, Rotter JI, …, Tobin MD. Nature Genetics, in press. Stage 1: GWAS in a total of n=48,201 individuals Stage 2: Follow-up of selected SNPs in 17 cohorts, including 34 SNPs in MESA (n=1,469)

  13. Analysis of family- and population-based samples in cohort genome-wide association studies. Manichaikul A, Chen WM, Williams K, Wong Q, Sale MM, Pankow JS, Tsai MY, Rotter JI, Rich SS, Mychaleckyj JC. Human Genetics, in press.

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