Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Pubmed ID: 33720349

Pubmed Central ID: PMC8128395

Journal: Genetics

Publication Date: May 17, 2021

MeSH Terms: Humans, Alleles, Gene Frequency, Genotype, Models, Statistical, Software, Models, Genetic, Phenotype, Linkage Disequilibrium, Genetics, Population

Grants: R01 HL120393, P30 DK020572, U01 HL120393, R01 HL117626, R01 HL113326, U54 GM104938, R01 AI132476, U01 MH105653, HHSN268201800001C, K01 HL129039, R01 DA037904, K01 HL135405, R01 HL142711, R01 HG009976, R03 HL154284, U01 HL137182, R01 HG007022, U01 HL117626, P01 HL045522, U01 CA182913

Authors: Eng C, Abecasis GR, Guo X, Smith NL, Reiner AP, Boerwinkle E, Lubitz SA, Cupples LA, Smith AV, Kooperberg C, Chasman DI, Irvin MR, Tiwari HK, Smith JA, Roden DM, Blangero J, Boehnke M, Kang HM, de Andrade M, Peloso GM, Montasser ME, Palmer ND, Scott LJ, Chen H, Montgomery CG, Barnard J, Ellinor PT, Barnes KC, Weiss ST, Mathias RA, LeFaive J, Burchard EG, Manichaikul AW, Kwong AM, Blackwell TW, Cade BE, Conomos MP, Gao Y, Kelly TN, Kim W, Mak ACY, Musani S, Qiao D, Shoemaker MB, Su JL, Weeks DE

Cite As: Kwong AM, Blackwell TW, LeFaive J, de Andrade M, Barnard J, Barnes KC, Blangero J, Boerwinkle E, Burchard EG, Cade BE, Chasman DI, Chen H, Conomos MP, Cupples LA, Ellinor PT, Eng C, Gao Y, Guo X, Irvin MR, Kelly TN, Kim W, Kooperberg C, Lubitz SA, Mak ACY, Manichaikul AW, Mathias RA, Montasser ME, Montgomery CG, Musani S, Palmer ND, Peloso GM, Qiao D, Reiner AP, Roden DM, Shoemaker MB, Smith JA, Smith NL, Su JL, Tiwari HK, Weeks DE, Weiss ST, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Analysis Working Group, Scott LJ, Smith AV, Abecasis GR, Boehnke M, Kang HM. Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries. Genetics 2021 May 17;218. (1).

Studies:

Abstract

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.