Although genome-wide association studies (GWAS) have identified statistically significant associations of common genetic variants with a variety of complex diseases and risk factors, these common variants typically explain only 5-10% of the genetic contribution to the phenotypic variance. The residual genetic variance, the missing heritability, may have several sources and is in part attributed to rare variants. As a means of performing association studies in large populations, a panel of variants derived from the exome sequencing of over 12,000 subjects has been used to create an Illumina Infinium genotyping array, the ExomeChip, which features non-synonymous, non-sense, and splice-site coding-region rare or infrequent variants. The analytic challenges and the sample size requirements for the high-quality analysis of these rare coding-region variants will require novel organizational structures and collaborations. In the GWAS era, one of the most successful and productive collaborations has been the CHARGE Consortium, which facilitated prospectively planned GWAS meta-analyses of multiple phenotypes among large cohort studies. The original five CHARGE cohorts and four collaborating cohorts have jointly-called ExomeChip genotype data on more than 50,000 participants. While the cohorts have been able to reallocate funding (with Institute approval) to generate the rare variant data, there are no additional funds available in existing sources to address analytic issues, to coordinate efforts, or to implement the analysis of the ExomeChip data. The CHARGE collaboration, which takes advantage of the hundreds of millions of dollars invested in these cohort studies, represents a unique resource for genetic studies. The phenotype-specific Working Groups take the lead in choosing and harmonizing phenotypes. The CHARGE Analysis Committee members not only provide recommendations for analytic methods, but they also solve analytic problems, conduct cohort-specific analysis, and implement consortium- wide prospectively planned meta-analyses. In the GWAS era, these methods and this organizational structure enabled the CHARGE investigators to accelerate the discovery of genetic association for common variants. Using the available ExomeChip coding-region genotype data from 9 well-phenotyped cohorts, the primary aim is to discover novel candidate genes and putative functional variants for high-priority heart, lung and blood phenotypes in multi-ethnic cohorts. The main activities include the selection of high-priority phenotypes, the appraisal and dissemination of analytic methods, the conduct of rare-variant analyses within each cohort, the meta-analysis of cohort-specific findings, both within and between ethnic groups, analysis of family data, pathway analyses, efforts to identify analytic problems, publication of findings, and the public release of source code and methods appraisals. We expect to complete at least 3-4 major analyses each year. The findings will be used to better understand biological pathways that may identify therapeutic targets.

Public Health Relevance

The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium has helped to accelerate the discovery of genetic variants associated with common diseases and risk factors. In the proposed application from the original 5 CHARGE cohorts and 4 collaborating cohorts-all with jointly- called ExomeChip genotype data, the analysis of rare and uncommon variants will identify new genetic loci associated with a variety of heart, lung, and blood-related phenotypes. The main contribution of these genetic studies will be the discovery of new biology, which may lead to future treatments. ecarlv5.doc

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL120393-02
Application #
8829696
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Papanicolaou, George
Project Start
2014-04-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Suri, Pradeep; Palmer, Melody R; Tsepilov, Yakov A et al. (2018) Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. PLoS Genet 14:e1007601
Ward-Caviness, Cavin K; Huffman, Jennifer E; Everett, Karl et al. (2018) DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. Blood 132:1842-1850
Wong, Jason Y Y; Margolis, Helene G; Machiela, Mitchell et al. (2018) Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study. Environ Int 116:239-247
Chen, Han; Cade, Brian E; Gleason, Kevin J et al. (2018) Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men. Am J Respir Cell Mol Biol 58:391-401
Xu, Jiayi; Bartz, Traci M; Chittoor, Geetha et al. (2018) Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function. Br J Nutr 120:1159-1170
Natarajan, Pradeep; Peloso, Gina M; Zekavat, Seyedeh Maryam et al. (2018) Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nat Commun 9:3391
Lumley, Thomas; Brody, Jennifer; Peloso, Gina et al. (2018) FastSKAT: Sequence kernel association tests for very large sets of markers. Genet Epidemiol 42:516-527
Irvin, Marguerite R; Sitlani, Colleen M; Noordam, Raymond et al. (2018) Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry. Pharmacogenomics J :
Floyd, J S; Sitlani, C M; Avery, C L et al. (2018) Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. Pharmacogenomics J 18:127-135
Seyerle, A A; Sitlani, C M; Noordam, R et al. (2018) Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology. Pharmacogenomics J 18:215-226

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