Citations 2
Genetic architecture of smoking: Evaluating rare variant contribution from deep whole-genome sequencing of up to 26,000 individuals
Jang, Seon-Kyeong , Arnett, Donna K. , Becker, Diane M. , Bis, Joshua C. , Bleecker, Eugene R., Fingerlin, Tasha E. , Haessler, Jeffrey, Heckbert, Susan R. , Hokanson, John E. , Judy, Renae , Justice, Anne E. , Kaplan, Robert C. , Kim, Wonji , Gladwin, Mark T. , Melander, Olle , Meyers, Deborah A. , Peljto, Anna L. , Qiao, Dandi , Reed, Robert M. , Reiner, Alex P. , Silverman, Edwin K. , Smith, Nicholas L. , Smith, Gustav, Smith, Albert V. , Tang, Weihong, Gordeuk, Victor R. , Yanek, Lisa R. , Yang, Ivana V. , Young, Kendra A. , Vrieze, Scott , Martin, Lisa , Smith, Albert V , Arnett, Donna K , Evans, Luke M. , Fialkowski, Allison , Blangero, John , Brody, Jennifer A. , Cupples, L. Adrienne , Damrauer, Scott M , David, Sean P. , Andrade, Mariza de , Gharib, Sina A. , Glahn, David C , Hwang, Shih‐Jen , Hyman, Matthew Craig , Kooperberg, Charles , Levy, Dan , Loos, Ruth J. F. , Manichaikul, Ani , Martin, Lisa W. , Nouraie, Mehdi , North, Kari E. , Oelsner, Elizabeth C. , Preuss, Michael , Psaty, Bruce M. , Rader, Daniel J , Rich, Stephen S. , Rotter, Jerome I. , Schwartz, David A. , Shadyab, Aladdin H , Taylor, Kent D. , Vasan, Ramachandran S. , Wang, Zhe , Wiggins, Kerri L. , Young, Kristin L. , Zhang, Yingze , Liu, Dajiang J. , Keller, Matthew C.
No container title available | May 6, 2021 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) program with whole genome sequence (WGS;~30X coverage).Method We grouped about 35 million genetic variants by their minor allele frequencies (MAF) and linkage disequilibrium (LD) and estimated SNP-heritability for age of smoking initiation (N = 14,747), cigarettes smoked per day (N = 15,425), smoking cessation (N = 17,871) and initiation (N = 26,340) using linear mixed model. Rare variant population structure is detected and adjusted for by permutation procedure. We estimated an upper bound for narrow-sense heritability for tobacco use using available pedigrees consisting of close relatives in TOPMed.Results Rare variants with MAF 0.1–0.01%, mostly from non-protein altering region, accounted for 26% of variation in age of initiation and 15% for cessation. Follow-up analysis indicated that about one-third of these rare variants contribtion is potentially confounded with rare variants structure even after adjusting for principal components. After further conservative adjustment of population structure, we estimated SNP-based heritability to be 0.21 (SE = 0.08) for age of initiation, 0.15 (0.06) for cigarettes per day, 0.21 (0.09) for cessation, and 0.24 (0.07) for initiation, 1.8–4.5 times higher than previous SNP-based estimates. Our pedigree-based upper-bound for SNP-based heritability ranged from 0.18–0.35.Conclusion The substantial contribution of rare variants for several smoking phenotypes sheds light on the missing heritability and genetic etiology of tobacco use. It also informs fine-mapping strategies since the majority of the rare variant contribution was located in non-coding regulatory regions.
Robust, flexible, and scalable tests for Hardy–Weinberg equilibrium across diverse ancestries
Kwong, Alan , Blackwell, Thomas W. , LeFaive, Jonathon , Barnes, Kathleen C. , Boerwinkle, Eric , Cade, Brian E. , Chen, Han , Conomos, Matthew P. , Eng, Celeste , Gao, Yan , Irvin, Marguerite R. , Kelly, Tanika N. , Kim, Wonji , Lubitz, Steven A. , Mathias, Rasika A. , Montasser, May E. , Musani, Solomon K., Palmer, Nicholette D, Qiao, Dandi , Reiner, Alex P. , Roden, Dan M. , Shoemaker, M. Benjamin , Smith, Jennifer A. , Smith, Nicholas L. , Lasky‐Su, Jessica , Tiwari, Hemant K., Weeks, Daniel E. , Group, TOPMed Analysis Working, Scott, Laura J. , Smith, Albert V. , Boehnke, Michael , Kang, Hyun Min , Palmer, Nicholette D. , Smith, Jennifer A , Lubitz, Steven A , Smith, Albert V , Kelly, Tanika N , Weeks, Daniel E , Palmer, Nicholette D , Mathias, Rasika A , Cade, Brian E , Lasky-Su, Jessica , Andrade, Mariza de , Barnard, John , Blangero, John , Burchard, Esteban G. , Chasman, Daniel I. , Cupples, L. Adrienne , Ellinor, Patrick T. , Guo, Xiuqing , Kooperberg, Charles , Mak, Angel C. Y. , Manichaikul, Ani , Montgomery, Courtney G. , Peloso, Gina M. , Roden, Dan M. , Weiss, Scott T. , Group, TOPMed Analysis Working, Abecasis, Gonçalo R.
Genetics | March 15, 2021 | Volume: 218 | Issue: 1 | Pages: No page available
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.