MESA Steering Committee Genetics Committee Update September 16

MESA Steering Committee Genetics Committee Update September 16, 2014 Jerome I. Rotter, MD

MESA Genetics Agenda Feb 5, 2014 6: 30 -8: 00 pm Fairfax Embassy Row Hotel 2100 Massachusetts Ave NW Ballroom 5: 30 -5: 50 Introduction 5: 50 -6: 00 Genetics P&P Update Dr. Post COMBInatorial BIOmarkers for subclinical atherosclerosis in MESA (COMBI-BIO-MESA): An overview of the MESA metabolomics project Dr. Olson/Dr. Durda 6: 00 -6: 30 7: 00 -7: 30 MESA Epigenetic Studies Bicc 1 is a genetic determinant of osteoblastogenesis and bone mineral density 7: 30 Adjourn 6: 30 -7: 00 Dr. Rotter/Dr. Rich Dr. Liu Dr. Farber

Genetics Dataset Availability Genetic dataset Available w/MESA ID from CC Available w/SHARe ID from db. Ga. P Affy 6. 0 No Yes Candidate Gene 1&2 Yes No No CARe IBC i. Select Yes Yes 96 SNP Yes No Metabochip Yes No No Exome Chip Yes Yes Exome Sequence Yes Yes Epigenomics methylation Yes No No Epigenomics expression Yes No No SHARe Principal Components Yes No 1000 G Imputation No Yes No Phenotype Updates Yes Yes

MESA SHARe Phenotype Working Groups • 22 MESA SHARe Phenotype Working Groups actively meet. • Since April 2010, 240 publication proposals were submitted from 20 different Phenotype Working Groups and SHARe Committees • 61 proposals use standard analysis plan developed by MESA SHARe Analysis Committee, 127 follow analysis outlined by consortia, and 55 use non-standard analysis as defined by the Working Group • 49 published papers from MESA SHARe (74 for all MESA Genetics) • Includes collaborations with CHS, 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, CHS, ARIC, AGES, Rotterdam, Jackson Heart, Family Heart Study Numbers above do not include ~18 CARe publications

MESA Genetics P&P Summary All SHARe Proposals approved Pen Draft Pending (Proposals approved; pen draft not yet approved) 348 240 224 159 8 0 Pen Draft approved 116 81 Published 74 49 Pen Draft approved; not yet published 42 32 Pending Pen Drafts not published 0 -3 months 18 9 3 -6 months 10 11 6 -9 months 12 4 9 -12 months 18 7 12+ months 166 12 Withdrawn

MESA SHARe Phenotype Working Groups Working Group # Paper Proposals Nutrition Lung Adiposity Blood Pressure Subclinical And Clinical CVD Fatty Acids Psychosocial Factors Biomarkers 29 19 18 18 18 16 16 13 Lipids Diabetes/Metabolic Syndrome AF/ECG Eye Pharmacogenetics LV Function/Structure Inflammation Metabochip Renal Mineral Metabolism Analysis Committee Cerebrovascular Disease/Neurology Sleep Cognitive 13 12 10 10 7 6 6 6 5 5 2 2 2 1

MESA Genetics P&P Committee Members • • • Wendy Post – Chair Christina Wassel Xiuqing Guo Stephen Rich Nancy Jenny Jim Pankow Yongmei Liu Lekki Frazier-Wood* Ani Manichaikul* * New members

MESA Genetics Published Papers: Recent Mesner et al. (Farber) SHARe J Clin Invest May 2014 G 218: BICC 1 SNP associations with bone mineral density (BMD) in the Multi-Ethnic Study of Atherosclerosis (MESA) Stambolian et al. (Li) SHARe Hum Mol Genet July 2013 G 219: Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX 1, a regulator of tissue-specific splicing, associated with refractive error. Manichaikul et al. SHARe Plos One March 2014 G 224: ID 3 SNP rs 11574 Associated with Atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA) Peloso et al. (Manichaikul) SHARe/Exome Am J Hum Genet Feb 2014 G 226: Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56, 000 whites and blacks

MESA Genetics Published Papers: Recent Reynolds SHARe Accepted Nature Communications G 236: Transcriptomic and Methylomic Signatures of Aging in Monocytes in the Multi-Ethnic Study of Atherosclerosis (MESA) Vinicius et al. (Palmas) SHARe AJHG Mar 2014 G 293: Gene-centric meta-analysis in 87, 736 individuals of European ancestry identifies multiple blood pressure related loci. Casas et al. SHARe J Acad Nutr Diet Apr 2014 G 310: Investigation of fat intake as a modulator of the association between a genetic risk score of obesity and BMI in the Genetics of Lipid Lowering drug Network (GOLDN) study and the Multi-ethnic Study of Atherosclerosis (MESA) Lo SHARe Accepted Statistics in Medicine G 274: Analysis of gene-environment interaction using a shrinkage estimator for longitudinal data in the Multi-Ethnic Study of Atherosclerosis Cohort

MESA Genetics Pen Drafts (recently approved) Title Lead Author Approval Date G 335: Plasma levels of s. IL-2 Rα: associations with clinical cardiovascular events and genome-wide association scan: CHS, Health ABC and MESA Durda Aug-14 G 337: Common and Rare Variant Associations with Circulating Hepatocyte Growth Factor Levels in the Multi-Ethnic Study of Atherosclerosis (MESA) Study Larson Aug-14 G 210: Common and Exonic Variants Associated with Biomarkers of Inflammation Allen Aug-14 G 229: Social Stress and DNA Methylation in Genes Related to Stress Reactivity and Inflammation: The Multi-Ethnic Study of Atherosclerosis Needham Jul-14 G 316: Meta-Analysis of Dietary Intake and Clock Variants Interactions with Metabolic Syndrome Traits Jul-14 Frazier-Wood G 324: Association of SELL polymorphisms with levels of circulating serum Lselectin and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA). Berardi Jul-14 G 333: Genome-wide association study of Lung Function and COPD in Hispanics Jul-14 Manichaikul

MESA Genetics Pen Drafts (recently approved) Title Lead Author Approval Date G 314: Detection of Cardiovascular risk variants using network analysis of multi-scale predictors of outcome in The Multi-Ethnic Study of Atherosclerosis (MESA) Study Sicotte Jun-14 G 320: Incidence of Age-Related Macular Degeneration in a Multi-Ethnic United States Population: The Multi-Ethnic Study of Atherosclerosis Klein Jun-14 G 164: Interactions of Consumption of Processed Meat with Beta Cell. Related Genetic Loci and Fasting Blood Glucose and Insulin in Individuals of European Descent participation of the Multi Ethnic Study of Atherosclerosis in a CHARGE Fretts May-14 G 285: Participation of MESA in “Replication of the novel hits for Go. NL lipid traits by CHARGE cohorts after 1 k. G imputation” Manichaikul May-14 G 129: GWAS for plasma N-3 fatty acids Smith May-14 G 135: Meta-analysis of genome-wide assoc. for plasma phospholipid Mozaffarian Apr-14 G 206: in silico replication of GWAS signals for glucose homeostasis traits from GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium in Guo case-controls sets of individuals with and without type 2 diabetes. Apr-14

MESA Genetics Pen Drafts (recently approved) Title Lead Author Approval Date G 214: Genome-Wide Association Study of saturated fatty acids (SFAs) in Chinese cohorts through the CHARGE Consortium – Participation of MESA in a CHARGE Zhu Plasma Fatty Acids Working Group Meta-analysis Apr-14 G 273: Role of Adhesion Molecules in Clinical and Subclinical Cardiovascular Disease: the Multi-Ethnic Study of Atherosclerosis (MESA) Berardi Apr-14 G 241: CHARGE Consortium Meta-Analysis for Type 2 Diabetes-Related Quantitative Traits: The Multi-Ethnic Study of Atherosclerosis Goodarzi Apr-14 G 255: Genetically-elevated lipoprotein levels and valve calcium - Mendelian Randomization in the CHARGE consortium Thanassoulis Mar-14 G 301: Association of sickle cell trait and chronic kidney disease in African. Americans: A pooled analysis Naik Mar-14 G 246: GWAS Meta-analysis of Circulating Phylloquinone Shea Mar-14 G 260: Genetic association study of chronic Mucus Hypersecretion in COPD: replication in MESA Caucasians Manichaikul Feb-14

Items to Discuss • Posting of summary results • Whole genome sequencing • Return of results to participants

MESA Heart. Go/ESP Ongoing Activities • Analyses and publication of data – Ongoing analyses of stroke, blood phenotypes, blood pressure, cardiac genes, etc – 69 papers cited NHLBI Exome Sequencing Project in Pub. Med (8/1/2014) • 34 used data from the Exome Variant Server (no phenotypes) • 5 obtained data from db. Ga. P • 29 ESP and ESP/CHARGE papers • Question of “termination” of ESP/Heart. GO, the ESP P&P Committee, and existing ESP data obtained from the db. Ga. P Exchange Area (not through separate db. Ga. P requests)

MESA Heart. Go/ESP Ongoing Activities • Transfer of ESP data to Coordinating Center – 404 MESA participants with exome sequencing data – Linked to MESA ID structure at Coordinating Center • Return of Results – Letter sent to NHLBI (Applebaum-Bowden, Fabstiz, Jaquish) July 29, 2014 requesting support for return of results – no response – Second letter sent August 19, 2014 – no response • NOT-HL-14 -029 (WGS in NHLBI cohorts) – MESA included (with ARIC and FHS); EA, AA and HIS only – More “return of results” issues

MESA Nutrition working group: Current projects • • Lekki Wood: The Epidemiology of Glyc. A and Glyc. B: new markers of inflammation derived from NMR data Collaborators: Stephen Rich, Jerome Rotter, Ida Chen, Mike Tsai & Donna Arnett Status: Non-MESA analyses completed; awaiting SHARe IDs for Glyc. A data Cassie Diep* & Lekki Wood: - Acculturation and plasma fatty acid concentrations in Chinese. American adults: Multi Ethnic Study of Atherosclerosis (MESA). Collaborators: Rozenn Lemaitre, Ani Manichukal, Pamela Lutsey, Brian Steffan, David St. Jules, Stephen S. Rich, Michael Y. Tsai & David Siscovick Status: Manuscript with co-authors Bertha Hidalgo* & Lekki Wood : – Ethnicity specific effects of an interaction between an obesity risk score and fat intake on BMI Collaborators: - Patricia Casas-Agustench, Stephen Rich, Matthew Allison, Donna Arnett Status: - Analysis underway Ski Chilton – Interactions between linoleic acid intake and FADS variants on phospholipid levels of n -6 and n-3 polyunsaturated fatty acids (PUFAs) by FADS variants in the Multi-ethnic Study on Atherosclerosis Collaborators: - Steve Rich, Ani Manichukal, Lyn Steffan, David St Jules, Rozenn Le. Maitre, Ida Chen, Mike Tsai & Lekki Wood (+ non MESA people) Status: - Awaiting R 01 funding. Michelle Averill & Chris Delaney: – The sodium-potassium ratio in the US diet: possible links with cardiovascular disease Collaborators: - Adam Drewnowski, Robyn Mc. Clelland, Emily Kurlak, Lekki Wood, Lyn Steffan, Edmond Kabagambe, Holly Mattix-Kramer, Ian De Boer, Theresa Nicklas Status: Preliminary results presentated Jennifer Davis* & Lekki Wood: – The sodium-potassium ratio in the US diet: possible links with cardiovascular disease Collaborators: - Lekki Wood, Matthew Allison (+ open to others) Status: - Draft proposal with working group Also several (> 10) consortium (CHARGE and SUNLIGHT) projects. *Trainee / postdoctoral fellow

MESA Nutrition working group: A recent paper • • Casas-Agustench et al, 2014, Saturated Fat Intake Modulates the Association between an Obesity Genetic Risk Score and Body Mass Index in Two US Populations, Jnl Acad Nutr Diet Objective: – • Populations: – – • – Significant interactions between total fat intake and the GRS on BMI (P for interaction = 0. 010, 0. 046, and 0. 002 in GOLDN, MESA, and meta-analysis, respectively). Significant interactions between SFA intake and GRS on BMI (P for interaction=0. 005, 0. 018, and <0. 001 in GOLDN, MESA, and meta-analysis, respectively). Conclusions: – • GRS summed from 55/60 known obesity risk alleles summed into a weighted score Models: BMI = GRS + SFA + GRS * SFA + age + gender + center + smoking + alcohol + hyperlipidemia medication + diabetes + physical + total energy intake Results: – • 783 Caucasian ancestry individuals from Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) 2, 035 Caucasian ancestry individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) Analysis: – – • To analyze whether the association between an obesity genetic risk score (GRS) and body mass index (BMI), is moderated by total fat and saturated fatty acid (SFA) intake. Although determining the causal direction requires further investigation, these findings suggest that potential dietary recommendations to reduce BMI effectively in populations with high obesity GRS would be to reduce total fat intake mainly by limiting SFAs Future Directions: – This interaction is being examined in non-Caucasian ancestry populations

Pharmacogenetics Working Group MESA analyses finished and results uploaded to CHARGE q QT and UAZ, Thiazides, Sulfonylureas and TCAs § Cross-sectional: MESA Caucasians, manuscript published in Pharmacogenomics Journal in 2013; § Longitudinal: MESA Caucasians and African Americans. q RR and TCAs: MESA Caucasians; q CV events and antihypertensive agents: MESA Caucasians and African Americans, manuscript in preparation. q Glucose/Insulin & statins and diuretics: MESA Caucasians and African Americans. q Lipids and thiazides: MESA Caucasians and African Americans. q Lipids and statins: MESA Caucasians § LDL: manuscript accepted for publication in Nature Communications; § HDL. q MI and statins: MESA Caucasians. q PCSK 9 variants and stroke, CHD and lipids: MESA Caucasians and African Americans.

Pharmacogenetic Meta-Analysis of GWAS of LDL Response to Statins Overall results from combined meta-analysis: GWAS SNPs identified within 4 loci: • APOE and LPA: replication of previous findings • SORT 1/CELSR 2/PSRC 1 and SLCO 1 B 1: novel GWAS findings Genome-Wide Conditional Analysis (GWCA) • 14 SNPs independently associated with LDL response • Together explain ~5% of variation in LDL response to statin treatment 4 significant SNPs and risk of Coronary Artery Disease (CAD): CARDIo. GRAMplus. C 4 D Genetic risk score: weaker LDL lowering response to statins and increased CAD risk (p = 2. 88 e-19)

MESA Lung Genetics WG • In progress: – CHARGE 1000 G pulmonary function GWAS – CHARGE Exome. Chip pulmonary function analysis – MESA GWAS of high attenuation area (subclinical ILD) on CT scan – Meta-analysis of percent emphysema on CT GWAS across three cohorts (MESA, Framingham, COPACETIC) – MESA Exome. Chip analysis of percent emphysema on CT scan • Submitted: – Meta-analysis of COPD GWAS for Hispanics from MESA and the Costa Rica Study (Juan Celedon)

Genome-wide study of percent emphysema on computed tomography in the general population: The Multi-Ethnic Study of Atherosclerosis Lung/SHARe Study Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH, Baumhauer H, Budoff M, Austin JH, Washko GR, Carr JJ, Kaufman JD, Pottinger T, Powell CA, Wijmenga C, Zanen P, Groen HJ, Postma DS, Wanner A, Rouhani FN, Brantly ML, Powell R, Smith BM, Rabinowitz D, Raffel LJ, Hinckley Stukovsky KD, Crapo JD, Beaty TH, Hokanson JE, Silverman EK, Dupuis J, O'Connor GT, Boezen HM, Rich SS, Barr RG. Am J Respir Crit Care Med. 2014 Feb 15; 189(4): 408 -18. In Hispanics Combined across race/ethnic groups

MESA Lipids Genetics WG • In progress: – CHARGE / Go. NL 1000 G lipids GWAS – CHARGE Lipids x Smoking GWIS – CHARGE Lipids x Alcohol GWIS – CHARGE / GLGC Exome. Chip lipids analysis • Submitted: – Go. NL 1000 G lipids GWAS with replication in CHARGE cohorts (including MESA)

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56, 000 whites and blacks Peloso GM, Auer PL, Bis JC, Voorman A, Morrison AC, …, Manichaikul A, …, NHLBI GO Exome Sequencing Project, …, Liu Y, Gudnason V, Wilson JG, van Duijn CM, Kooperberg C, Rich SS, Psaty BM, Rotter JI, O'Donnell CJ, Rice K, Boerwinkle E, Kathiresan S, Cupples LA. Am J Hum Genet. 2014 Feb 6; 94(2): 223 -32.

MESA Epigenomic and Transcriptomic Studies Data generated: 3 New grants submission MESA mi. RNA sequencing grant: scored 13 (2 nd percentile) on the first submission MESA epigenetic working groups: DNA methylomic and transcriptomic profiling of 1, 264 monocytes & 310 T cell samples, pluse mi. RNA-seq and m. RNA-seq on a subset of 373 monocyte samples Traits: Aging, Obestiy, DM/CVD, smoking, HTN, sleep, . . Participate in consortia: CHARG gene expression CHARG epigenetics

MESA Epigenomic and Transcriptomic Studies Publications: Methylomics of gene expression. HMG 2013 Methylomic profiles of aging. Nature Communication, in press Transciptomic profiles of aging. Genome Biology, under revision Epigenetic study of SES. PNAS, under revision Transciptomic profiles of Obesity, and DM & subclical CVD. Diabetes, under review Abstracts: Epignetic study of smoking. AHA Scientific Sessions 2014, oral presentation

Cardio. Metabo. Chip Working Group • MESA Adhesion – – – Sue Bielinski, Chair Jim Pankow Michele Sale Weihong Tang Paul Decker Christina Wassel • MESA CC • MESA Air – Joel Kaufman – Sverre Vedal • MESA Genetics – – Jerry Rotter Kent Taylor Ida Chen Xiuqing Chen – Kayleen Williams Group convenes monthly via conference call to review manuscript proposals.

Cardio. Metabo. Chip Working Group List of Approved Manuscript Proposals Using Cardio. Metabo. Chip Data 1 Generalization and fine mapping of previously identified QT loci to multi-ethnic populations (Christy Avery et al) 2 Genetic association of kidney traits in African American and Hispanic individuals using the Metabo. Chip array: Discovery and Fine Mapping in the Population Architecture Using Genomics in Epidemiology (PAGE) Consortium (Christina Wassel et al ) 3 Generalization and fine mapping of previously identified PR loci to multi-ethnic populations (Amanda Seyerle et al ) 4 Sex heterogeneity assessment of variants identified through generalization and fine-mapping analysis of previously identified waist related trait loci in a Metabochip-wide analysis of multiple ancestry populations (Sachiko Yoneyama et al ) 5 Genetic analyses of obstructive sleep apnea and related traits in The Multi-Ethnic Study of Atherosclerosis (MESA) (Brian Cade et al) 6 Associations of Single-Nucleotide Polymorphisms (SNPs) in Nitric Oxide Synthase (NOS 3) and Arterial Hemodynamic Parameters Derived from the Radial Artery Blood Pressure Waveform (Daniel Duprez et al) 7 Genetic and epigenetic relationships between sleep timing and type 2 diabetes in The Multi-Ethnic Study of Atherosclerosis (MESA) (Jacqueline Lane et al) 8 Participation of MESA in "Fine-mapping of Metabochip lipids regions in global populations from the PAGE consortium“(Ani Manichaikul et al) 9 Metabochip analyses for Age of Natural Menopause - The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA Family joining as discovery cohort in the PAGE Consortium (Leslie Raffel et al) 10 Association of SELL Polymorphisms With Levels of Circulating Serum L-Selectin: The Multi-Ethnic Study of Atherosclerosis (MESA) (Ceci Berardi et al) 11 Common and Rare Variant Associations with Circulating Hepatocyte Growth Factor Levels in The Multi-Ethnic Study of Atherosclerosis (MESA) Study (Nick Larson et al) 12 Association of Scavenger Receptor Class B Type I (SCARB 1) rs 1084677 with Inflammatory Biomarkers and Subclinical Atherosclerosis and Incident Cardiovascular Disease: Multi-Ethnic Study of Atherosclerosis (Ani Manichaikul et al)

MESA Adhesion Research Team Site Name Role Suzette J. Bielinski, Ph. D Principal Investigator Mariza de Andrade, Ph. D Statistician Paul A. Decker, MS Statistician Phil Kirsch, MPH Statistical Programmer Hughes Sicotte, Ph. D Bioinformatician Nicholas B. Larson, Ph. D Research Associate Cecilia Berardi, MD Post-doctoral Fellow Michael Tsai, MD MESA Core Lab Naomi Hanson, MS MESA Core Lab James S. Pankow, Ph. D Co-Investigator Weihong Tang, Ph. D Co-Investigator University of Virginia Michele Sale, Ph. D MESA Genotype Lab University of Pittsburgh Christina Wassel, Ph. D Co-Investigator Mayo Clinic, Rochester University of Minnesota 28

MESA Adhesion Updates • 15 adhesion proteins measured at exam 2 and HGF at exam 1 • Merged datasets completed – MESA Cohort: Cardio. Metabo. Chip, IBC Panel, Exome Chip – MESA 2880: also includes Candidate Gene SNPs • Custom Panel: ABO SNPs and adhesion e. QTL variants (currently being genotyped) 29