publication . Other literature type . Article . 2020

Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts.

Elizabeth T. Cirulli; Simon White; Robert W. Read; Gai Elhanan; William J. Metcalf; Francisco Tanudjaja; Donna M. Fath; Efren Sandoval; Magnus Isaksson; Karen A. Schlauch; ...
Open Access
  • Published: 28 Jan 2020
  • Publisher: Springer Science and Business Media LLC
Abstract
Understanding the impact of rare variants is essential to understanding human health. We analyze rare (MAF < 0.1%) variants against 4264 phenotypes in 49,960 exome-sequenced individuals from the UK Biobank and 1934 phenotypes (1821 overlapping with UK Biobank) in 21,866 members of the Healthy Nevada Project (HNP) cohort who underwent Exome + sequencing at Helix. After using our rare-variant-tailored methodology to reduce test statistic inflation, we identify 64 statistically significant gene-based associations in our meta-analysis of the two cohorts and 37 for phenotypes available in only one cohort. Singletons make significant contributions to our results, and ...
Subjects
free text keywords: Science, Q, Article, Genetic association study, Rare variants, Next-generation sequencing, Genetics research, General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry
Related Organizations
62 references, page 1 of 5

1.Richardson, T. G., Harrison, S., Hemani, G. & Davey Smith, G. An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome. Elife 8, e43657 (2019).

Khera, AV. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat. Genet.. 2018; 50: 1219-1224 [OpenAIRE] [PubMed] [DOI]

Krapohl, E. Phenome-wide analysis of genome-wide polygenic scores. Mol. Psychiatry. 2016; 21: 1188-1193 [OpenAIRE] [PubMed] [DOI]

Long, T. Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nat. Genet.. 2017; 49: 568-578 [OpenAIRE] [PubMed] [DOI]

Zhu, Q. A genome-wide comparison of the functional properties of rare and common genetic variants in humans. Am. J. Hum. Genet.. 2011; 88: 458-468 [OpenAIRE] [PubMed] [DOI]

Nejentsev, S, Walker, N, Riches, D, Egholm, M, Todd, JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 2009; 324: 387-389 [OpenAIRE] [PubMed] [DOI]

Liu, P. Reanalysis of clinical exome sequencing data. N. Engl. J. Med.. 2019; 380: 2478-2480 [OpenAIRE] [PubMed] [DOI]

Bick, David, Jones, Marilyn, Taylor, Stacie L, Taft, Ryan J, Belmont, John. Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases. Journal of Medical Genetics. 2019; 56 (12): 783-791 [OpenAIRE] [PubMed] [DOI]

Ramoni, RB. The undiagnosed diseases network: accelerating discovery about health and disease. Am. J. Hum. Genet.. 2017; 100: 185-192 [OpenAIRE] [PubMed] [DOI]

Smedley, D. Next-generation diagnostics and disease-gene discovery with the Exomiser. Nat. Protoc.. 2015; 10: 2004-2015 [OpenAIRE] [PubMed] [DOI]

Liu, C. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat. Genet.. 2016; 48: 1162-1170 [OpenAIRE] [PubMed] [DOI]

Do, R. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015; 518: 102-106 [OpenAIRE] [PubMed] [DOI]

Flannick, J. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature. 2019; 570: 71-76 [OpenAIRE] [PubMed] [DOI]

14.Van Hout, C. V. et al. Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank. bioRxiv 572347, 10.1101/572347. (2019).

15.Grzymski, J. J. et al. Population health genetic screening for tier 1 inherited diseases in northern Nevada: 90% of at-risk carriers are missed. bioRxiv 650549, 10.1101/650549 (2019).

62 references, page 1 of 5
Abstract
Understanding the impact of rare variants is essential to understanding human health. We analyze rare (MAF < 0.1%) variants against 4264 phenotypes in 49,960 exome-sequenced individuals from the UK Biobank and 1934 phenotypes (1821 overlapping with UK Biobank) in 21,866 members of the Healthy Nevada Project (HNP) cohort who underwent Exome + sequencing at Helix. After using our rare-variant-tailored methodology to reduce test statistic inflation, we identify 64 statistically significant gene-based associations in our meta-analysis of the two cohorts and 37 for phenotypes available in only one cohort. Singletons make significant contributions to our results, and ...
Subjects
free text keywords: Science, Q, Article, Genetic association study, Rare variants, Next-generation sequencing, Genetics research, General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry
Related Organizations
62 references, page 1 of 5

1.Richardson, T. G., Harrison, S., Hemani, G. & Davey Smith, G. An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome. Elife 8, e43657 (2019).

Khera, AV. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat. Genet.. 2018; 50: 1219-1224 [OpenAIRE] [PubMed] [DOI]

Krapohl, E. Phenome-wide analysis of genome-wide polygenic scores. Mol. Psychiatry. 2016; 21: 1188-1193 [OpenAIRE] [PubMed] [DOI]

Long, T. Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nat. Genet.. 2017; 49: 568-578 [OpenAIRE] [PubMed] [DOI]

Zhu, Q. A genome-wide comparison of the functional properties of rare and common genetic variants in humans. Am. J. Hum. Genet.. 2011; 88: 458-468 [OpenAIRE] [PubMed] [DOI]

Nejentsev, S, Walker, N, Riches, D, Egholm, M, Todd, JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 2009; 324: 387-389 [OpenAIRE] [PubMed] [DOI]

Liu, P. Reanalysis of clinical exome sequencing data. N. Engl. J. Med.. 2019; 380: 2478-2480 [OpenAIRE] [PubMed] [DOI]

Bick, David, Jones, Marilyn, Taylor, Stacie L, Taft, Ryan J, Belmont, John. Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases. Journal of Medical Genetics. 2019; 56 (12): 783-791 [OpenAIRE] [PubMed] [DOI]

Ramoni, RB. The undiagnosed diseases network: accelerating discovery about health and disease. Am. J. Hum. Genet.. 2017; 100: 185-192 [OpenAIRE] [PubMed] [DOI]

Smedley, D. Next-generation diagnostics and disease-gene discovery with the Exomiser. Nat. Protoc.. 2015; 10: 2004-2015 [OpenAIRE] [PubMed] [DOI]

Liu, C. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat. Genet.. 2016; 48: 1162-1170 [OpenAIRE] [PubMed] [DOI]

Do, R. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015; 518: 102-106 [OpenAIRE] [PubMed] [DOI]

Flannick, J. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature. 2019; 570: 71-76 [OpenAIRE] [PubMed] [DOI]

14.Van Hout, C. V. et al. Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank. bioRxiv 572347, 10.1101/572347. (2019).

15.Grzymski, J. J. et al. Population health genetic screening for tier 1 inherited diseases in northern Nevada: 90% of at-risk carriers are missed. bioRxiv 650549, 10.1101/650549 (2019).

62 references, page 1 of 5
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