MESA Genetics and MESA SHARe PP Activities September
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. • Since April 2010, 75 publication proposals, and 16 pen drafts were submitted from 17 different Phenotype Working Groups and SHARe Committees • 19 proposals 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, Health. ABC, SUNLIGHT, CKDGen, FIND, WHI, Family Heart Study, Genestar, Diabetic Heart Study, Framingham, AGES
MESA SHARe Phenotype Working Groups Working Group Nutrition Blood Pressure AF/ECG Adiposity Fatty Acids WG Eye Biomarkers Subclinical Athero Lipids WG Diabetes/Metabolic Syndrome Psychosocial Factors Lung WG Analysis Committee LV Structure/Function Renal Clinical CVD WG Inflammation # Paper Proposals 11 9 8 7 6 5 5 4 3 3 2 2 2 1 1
MESA SHARe Published Papers (Goodarzi) Song et al. Replication Published Nature Dec 2010 CRTC 3 links catecholamine signalling to energy balance (Palmas) Ehret et al. Replication Published Nature Sept 2011 Common polymorphisms impacting blood pressure and cardiovascular disease in diverse populations highlight novel biological pathways (Palmas) Wain et al. Replication Accepted Nature Genetics Aug 2011 Genome wide association study identifies six new loci influencing pulse pressure and mean arterial pressure Manichaikul et al. Methods Accepted Human Genetics July 2011 Analysis of Family- and Population-Based Samples in Cohort Genome-Wide Association Studies
MESA SHARe Published Papers Lemaitre et al. Meta-analysis Accepted PLOS Genetics, July 2011 Genetic loci associated with plasma phospholipid n-3 fatty acids. A meta-analysis of Genome-wide Associations from the CHARGE Consortium (Herrington) O’Donnell et al. Replication In Press Circulation July 2011 Genome-wide association study for coronary artery calcification with follow up in myocardial infarction. (Manichaikul) Artigas et al. Meta-analysis Accepted Nature Genetics July 2011 Genome wide Association and large scale follow up identifies 16 novel loci for lung function.
MESA SHARe Pen Drafts Topic Genome-Wide Association Study for Retinal Arteriolar Caliber: The Multi-Ethnic Study of Atherosclerosis Genome-Wide Association Study of Fasting Glucose and Fasting Insulin: The Multi-Ethnic Study of Atherosclerosis Genome Wide Association Analysis of Plasminogen Activator Inhibitor Type 1 Levels in MESA: Collaboration with CHARGE Genome-wide Association Study of Ankle Brachial Index and Peripheral Arterial Disease in the Caucasians from the CHARGE consortium Genome-wide association study of valvular and aortic calcium: Participation of the Multi- Ethnic Study of Atherosclerosis (MESA) in a Consortium Analysis Meta-analysis of genome-wide association data for resting heart rate: the HRgen Consortium Population structure of Hispanic American samplesin the Multi-Ethnic Study of Atherosclerosis Genome-wide association studies to elucidate novel genetic predictors of depressive symptoms – GWAS in Caucasians from the Multi-Ethnic Study of Atherosclerosis Lookup in the Multi Ethnic Study of Atherosclerosis SHARe GWAS of HDAC genes for association with adiposity Lead Author Approval Date Xueling Sim May 2011 Laura J. Rasmussen. Torvik April 2011 Josyf C. Mychaleckyj August 2011 Christina Wassel Catherine Y. Campbell July 2011 Kathleen F. Kerr July 2011 Ani Manichaikul under review Erin J Bakshis August 2011 Mark O Goodarzi March 2011 July 2011
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.
CRTC 3 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). High fat diet Fat mass on high fat diet • • • CRTC 3 knockout mice are protected against diet-induced obesity S 72 N is a common human variant. 72 N found to have increased CRTC 3 activity in vitro. MACAD: 72 N associated with increased weight, increased BMI, and increased hip circumference MESA Hispanics: 72 N associated with increased BSA and a trend to increased weight Association not observed in non-Hispanic whites: MESA, CHARGE, GIANT 72 N is minor allele in Hispanics, major allele in non-Hispanic whites
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk The 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<5 E-09). Of them, 16 loci were novel; 6 contain genes previously known or suspected to regulate blood pressure (GUCY 1 A 3–GUCY 1 B 3, NPR 3–C 5 orf 23, ADM, FURIN–FES, GOSR 2, GNAS–EDN 3); 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.
Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure The 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) PP • • MAP 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 4 q 12 near CHIC 2, 7 q 22. 3 near PIK 3 CG, 8 q 24. 12 in NOV and 11 q 24. 3 near ADAMTS 8), 2 new MAP loci (3 p 21. 31 in MAP 4 and 10 q 25. 3 near ADRB 1) and 1 locus associated with both traits(2 q 24. 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.
Genetic Loci Associated with Plasma Phospholipid n-3 Fatty Acids: A Meta-Analysis of Genome-wide Association Studies from the CHARGE Consortium Lemaitre, Tanaka, Tang, Manichaikul, Foy et al PLo. S Genet. 2011 Jul; 7: e 1002193. • ALA, EPA, DHA, DPA • Meta-analysis of GWAS in MESA, CHS, ARIC, CARDIA, In. CHIANTI • 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 Ø Implies more benefit of plant n-3 consumption (eg canola oil) in carriers of major allele.
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)
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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