Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults

Fang Chen; Jing He; Jianqi Zhang; Gary K Chen; Venetta Thomas; Christine B Ambrosone; Elisa V Bandera; Sonja I Berndt; Leslie Bernstein; William J Blot; Qiuyin Cai; John Carpten; Graham Casey; Stephen J Chanock; Iona Cheng; Lisa Chu; Sandra L Deming; W Ryan Driver; Phyllis Goodman; Richard B Hayes; Anselm J M Hennis; Ann W Hsing; Jennifer J Hu; Sue A Ingles; Esther M John; Rick A Kittles; Suzanne Kolb; M Cristina Leske; Robert C Millikan; Kristine R Monroe; Adam Murphy; Barbara Nemesure; Christine Neslund-Dudas; Sarah Nyante; Elaine A Ostrander; Michael F Press; Jorge L Rodriguez-Gil; Ben A Rybicki; Fredrick Schumacher; Janet L Stanford; Lisa B Signorello; Sara S Strom; Victoria Stevens; David Van Den Berg; Zhaoming Wang; John S Witte; Suh-Yuh Wu; Yuko Yamamura; Wei Zheng; Regina G Ziegler; Alexander H Stram; Laurence N Kolonel; Loïc Le Marchand; Brian E Henderson; Christopher A Haiman; Daniel O Stram

doi:10.1371/journal.pone.0131106

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Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults

Journal article

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Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults

Fang Chen, Jing He, Jianqi Zhang, Gary K Chen, Venetta Thomas, Christine B Ambrosone, Elisa V Bandera, Sonja I Berndt, Leslie Bernstein, William J Blot, …

PloS one, Vol.10(6), pp.e0131106-e0131106

2015

DOI: https://doi.org/10.1371/journal.pone.0131106

PMCID: PMC4488332

PMID: 26125186

Appears in UM Open Access Research Published in PloS

Abstract

Regression Analysis

Phenotype

Humans

Polymorphism, Single Nucleotide - genetics

Female

Genotype

Linear Models

Male

Models, Genetic

African Continental Ancestry Group - genetics

Genome-Wide Association Study - methods

Body Height - genetics

Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.189 Genome Studies; 1.189.455 Genome-Wide Association Studies
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults
Creators: Fang Chen - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Jing He - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Jianqi Zhang - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Gary K Chen - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Venetta Thomas - Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL, United States of America
Christine B Ambrosone - Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, United States of America
Elisa V Bandera - The Cancer Institute of New Jersey, New Brunswick, NJ, United States of America
Sonja I Berndt - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
Leslie Bernstein - Division of Cancer Etiology, Department of Population Science, Beckman Research Institute, City of Hope, CA, United States of America
William J Blot - International Epidemiology Institute, Rockville, MD, United States of America; Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University and the Vanderbilt-Ingram Cancer Center, Nashville, TN, United States of America
Qiuyin Cai - Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University and the Vanderbilt-Ingram Cancer Center, Nashville, TN, United States of America
John Carpten - The Translational Genomics Research Institute, Phoenix, AZ, United States of America
Graham Casey - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Stephen J Chanock - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
Iona Cheng - Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, United States of America
Lisa Chu - Cancer Prevention Institute of California, Fremont, CA, United States of America
Sandra L Deming - Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University and the Vanderbilt-Ingram Cancer Center, Nashville, TN, United States of America
W Ryan Driver - Epidemiology Research Program, American Cancer Society, Atlanta, GA, United States of America
Phyllis Goodman - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
Richard B Hayes - Division of Epidemiology, Department of Environmental Medicine, New York University Langone Medical Center, New York, NY, United States of America
Anselm J M Hennis - Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados; Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, United States of America
Ann W Hsing - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
Jennifer J Hu - Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL, United States of America
Sue A Ingles - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Esther M John - Cancer Prevention Institute of California, Fremont, CA, United States of America; Division of Epidemiology, Department of Health Research & Policy, Stanford University School of Medicine and Stanford Cancer Institute, Stanford, CA, United States of America
Rick A Kittles - Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America
Suzanne Kolb - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
M Cristina Leske - Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, United States of America
Robert C Millikan - Department of Epidemiology, Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, United States of America
Kristine R Monroe - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Adam Murphy - Department of Urology, Northwestern University, Chicago, IL, United States of America
Barbara Nemesure - Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, United States of America
Christine Neslund-Dudas - Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, United States of America
Sarah Nyante - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
Elaine A Ostrander - Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States of America
Michael F Press - Department of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Jorge L Rodriguez-Gil - Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL, United States of America
Ben A Rybicki - Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, United States of America
Fredrick Schumacher - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Janet L Stanford - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
Lisa B Signorello - Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States of America
Sara S Strom - Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America
Victoria Stevens - Epidemiology Research Program, American Cancer Society, Atlanta, GA, United States of America
David Van Den Berg - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Zhaoming Wang - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
John S Witte - Institute for Human Genetics, Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America
Suh-Yuh Wu - Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, United States of America
Yuko Yamamura - Institute for Human Genetics, Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America
Wei Zheng - Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University and the Vanderbilt-Ingram Cancer Center, Nashville, TN, United States of America
Regina G Ziegler - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
Alexander H Stram - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Laurence N Kolonel - Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, United States of America
Loïc Le Marchand - Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, United States of America
Brian E Henderson - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Christopher A Haiman - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Daniel O Stram - Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
Publication Details: PloS one, Vol.10(6), pp.e0131106-e0131106
Publisher: United States
Grant note: U10 CA037429 / NCI NIH HHS 5U19CA148537 / NCI NIH HHS U01 HG004802 / NHGRI NIH HHS 5R01CA165862 / NCI NIH HHS R01 ES011126 / NIEHS NIH HHS R01 CA092447 / NCI NIH HHS 1U01HG007397-01 / NHGRI NIH HHS R01 CA165862 / NCI NIH HHS T32 GM008692 / NIGMS NIH HHS UM1 CA182883 / NCI NIH HHS U19 CA148537 / NCI NIH HHS U01 HG007397 / NHGRI NIH HHS RC2CA148085 / NCI NIH HHS UG1 CA189974 / NCI NIH HHS RC2 CA148085 / NCI NIH HHS U01HG004802-04 / NHGRI NIH HHS 15UB-8402 / PHS HHS
Academic Unit: Miller School of Medicine; UMMG Department of Public Health Sciences Research
Language: English
Resource Type: Journal article
PMID: 26125186
PMCID: PMC4488332
Record Identifier: 991031561003002976