Variant-specific inflation factors for assessing population stratification at the phenotypic variance level
Authors: Sofer Tamar , Zheng Xiuwen , Laurie Cecelia A. , Gogarten Stephanie M. , Brody Jennifer A. , Conomos Matthew P. , Bis Joshua C. , Thornton Timothy A. , Szpiro Adam , O’Connell Jeffrey R. , Lange Ethan M. , Gao Yan , Cupples L. Adrienne , Psaty Bruce M. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Abe Namiko , Abecasis Gonçalo , Aguet Francois , Albert Christine , Almasy Laura , Alonso Alvaro , Ament Seth , Anderson Peter , Anugu Pramod , Applebaum-Bowden Deborah , Ardlie Kristin , Arking Dan , Arnett Donna K. , Ashley-Koch Allison , Aslibekyan Stella , Assimes Tim , Auer Paul , Avramopoulos Dimitrios , Ayas Najib , Balasubramanian Adithya , Barnard John , Barnes Kathleen , Barr R. Graham , Barron-Casella Emily , Barwick Lucas , Beaty Terri , Beck Gerald , Becker Diane , Becker Lewis , Beer Rebecca , Beitelshees Amber , Benjamin Emelia , Benos Takis , Bezerra Marcos , Bielak Larry , Bis Joshua , Blackwell Thomas , Blangero John , Boerwinkle Eric , Bowden Donald W. , Bowler Russell , Brody Jennifer , Broeckel Ulrich , Broome Jai , Brown Deborah , Bunting Karen , Burchard Esteban , Bustamante Carlos , Buth Erin , Cade Brian , Cardwell Jonathan , Carey Vincent , Carrier Julie , Carty Cara , Casaburi Richard , Romero Juan P. Casas , Casella James , Castaldi Peter , Chaffin Mark , Chang Christy , Chang Yi-Cheng , Chasman Daniel , Chavan Sameer , Chen Bo-Juen , Chen Wei-Min , Chen Yii-Der Ida , Cho Michael , Choi Seung Hoan , Chuang Lee-Ming , Chung Mina , Chung Ren-Hua , Clish Clary , Comhair Suzy , Conomos Matthew , Cornell Elaine , Correa Adolfo , Crandall Carolyn , Crapo James , Cupples L. Adrienne , Curran Joanne , Curtis Jeffrey , Custer Brian , Damcott Coleen , Darbar Dawood , David Sean , Davis Colleen , Daya Michelle , de Andrade Mariza , Fuentes Lisa de las , de Vries Paul , DeBaun Michael , Deka Ranjan , DeMeo Dawn , Devine Scott , Dinh Huyen , Doddapaneni Harsha , Duan Qing , Dugan-Perez Shannon , Duggirala Ravi , Durda Jon Peter , Dutcher Susan K. , Eaton Charles , Ekunwe Lynette , El Boueiz Adel , Ellinor Patrick , Emery Leslie , Erzurum Serpil , Farber Charles , Farek Jesse , Fingerlin Tasha , Flickinger Matthew , Fornage Myriam , Franceschini Nora , Frazar Chris , Fu Mao , Fullerton Stephanie M. , Fulton Lucinda , Gabriel Stacey , Gan Weiniu , Gao Shanshan , Gao Yan , Gass Margery , Geiger Heather , Gelb Bruce , Geraci Mark , Germer Soren , Gerszten Robert , Ghosh Auyon , Gibbs Richard , Gignoux Chris , Gladwin Mark , Glahn David , Gogarten Stephanie , Gong Da-Wei , Goring Harald , Graw Sharon , Gray Kathryn J. , Grine Daniel , Gross Colin , Gu C. Charles , Guan Yue , Guo Xiuqing , Gupta Namrata , Haas David M. , Haessler Jeff , Hall Michael , Han Yi , Hanly Patrick , Harris Daniel , Hawley Nicola L. , He Jiang , Heavner Ben , Heckbert Susan , Hernandez Ryan , Herrington David , Hersh Craig , Hidalgo Bertha , Hixson James , Hobbs Brian , Hokanson John , Hong Elliott , Hoth Karin , Hsiung Chao , Hu Jianhong , Hung Yi-Jen , Huston Haley , Hwu Chii Min , Irvin Marguerite Ryan , Jackson Rebecca , Jain Deepti , Jaquish Cashell , Johnsen Jill , Johnson Andrew , Johnson Craig , Johnston Rich , Jones Kimberly , Kang Hyun Min , Kaplan Robert , Kardia Sharon , Kelly Shannon , Kenny Eimear , Kessler Michael , Khan Alyna , Khan Ziad , Kim Wonji , Kimoff John , Kinney Greg , Konkle Barbara , Kooperberg Charles , Kramer Holly , Lange Christoph , Lange Ethan , Lange Leslie , Laurie Cathy , Laurie Cecelia , LeBoff Meryl , Lee Sandra , Lee Wen-Jane , LeFaive Jonathon , Levine David , Levy Dan , Lewis Joshua , Li Xiaohui , Li Yun , Lin Henry , Lin Honghuang , Lin Xihong , Liu Simin , Liu Yongmei , Liu Yu , Loos Ruth J. F. , Lubitz Steven , Lunetta Kathryn , Luo James , Magalang Ulysses , Mahaney Michael , Make Barry , Manichaikul Ani , Manning Alisa , Manson JoAnn , Martin Lisa , Marton Melissa , Mathai Susan , Mathias Rasika , May Susanne , McArdle Patrick , McDonald Merry-Lynn , McFarland Sean , McGarvey Stephen , McGoldrick Daniel , McHugh Caitlin , McNeil Becky , Mei Hao , Meigs James , Menon Vipin , Mestroni Luisa , Metcalf Ginger , Meyers Deborah A. , Mignot Emmanuel , Mikulla Julie , Min Nancy , Minear Mollie , Minster Ryan L. , Mitchell Braxton D. , Moll Matt , Momin Zeineen , Montasser May E. , Montgomery Courtney , Muzny Donna , Mychaleckyj Josyf C. , Nadkarni Girish , Naik Rakhi , Naseri Take , Natarajan Pradeep , Nekhai Sergei , Nelson Sarah C. , Neltner Bonnie , Nessner Caitlin , Nickerson Deborah , Nkechinyere Osuji , North Kari , O’Connell Jeff , O’Connor Tim , Ochs-Balcom Heather , Okwuonu Geoffrey , Pack Allan , Paik David T. , Palmer Nicholette , Pankow James , Papanicolaou George , Parker Cora , Peloso Gina , Peralta Juan Manuel , Perez Marco , Perry James , Peters Ulrike , Peyser Patricia , Phillips Lawrence S. , Pleiness Jacob , Pollin Toni , Post Wendy , Becker Julia Powers , Boorgula Meher Preethi , Preuss Michael , Psaty Bruce , Qasba Pankaj , Qiao Dandi , Qin Zhaohui , Rafaels Nicholas , Raffield Laura , Rajendran Mahitha , Ramachandran Vasan S. , Rao D. C. , Rasmussen-Torvik Laura , Ratan Aakrosh , Redline Susan , Reed Robert , Reeves Catherine , Regan Elizabeth , Reiner Alex , Reupena Muagututi’a Sefuiva , Rice Ken , Rich Stephen , Robillard Rebecca , Robine Nicolas , Roden Dan , Roselli Carolina , Rotter Jerome , Ruczinski Ingo , Runnels Alexi , Russell Pamela , Ruuska Sarah , Ryan Kathleen , Sabino Ester Cerdeira , Saleheen Danish , Salimi Shabnam , Salvi Sejal , Salzberg Steven , Sandow Kevin , Sankaran Vijay G. , Santibanez Jireh , Schwander Karen , Schwartz David , Sciurba Frank , Seidman Christine , Seidman Jonathan , Sériès Frédéric , Sheehan Vivien , Sherman Stephanie L. , Shetty Amol , Shetty Aniket , Sheu Wayne Hui-Heng , Shoemaker M. Benjamin , Silver Brian , Silverman Edwin , Skomro Robert , Smith Albert Vernon , Smith Jennifer , Smith Josh , Smith Nicholas , Smith Tanja , Smoller Sylvia , Snively Beverly , Snyder Michael , Sofer Tamar , Sotoodehnia Nona , Stilp Adrienne M. , Storm Garrett , Streeten Elizabeth , Su Jessica Lasky , Sung Yun Ju , Sylvia Jody , Szpiro Adam , Taliun Daniel , Tang Hua , Taub Margaret , Taylor Kent D. , Taylor Matthew , Taylor Simeon , Telen Marilyn , Thornton Timothy A. , Threlkeld Machiko , Tinker Lesley , Tirschwell David , Tishkoff Sarah , Tiwari Hemant , Tong Catherine , Tracy Russell , Tsai Michael , Vaidya Dhananjay , Van Den Berg David , VandeHaar Peter , Vrieze Scott , Walker Tarik , Wallace Robert , Walts Avram , Wang Fei Fei , Wang Heming , Wang Jiongming , Watson Karol , Watt Jennifer , Weeks Daniel E. , Weinstock Joshua , Weir Bruce , Weiss Scott T. , Weng Lu-Chen , Wessel Jennifer , Willer Cristen , Williams Kayleen , Williams L. Keoki , Wilson Carla , Wilson James , Winterkorn Lara , Wong Quenna , Wu Joseph , Xu Huichun , Yanek Lisa , Yang Ivana , Yu Ketian , Zekavat Seyedeh Maryam , Zhang Yingze , Zhao Snow Xueyan , Zhao Wei , Zhu Xiaofeng , Zody Michael , Zoellner Sebastian , Rice Kenneth M. 
Published: June 2021

In modern Whole Genome Sequencing (WGS) epidemiological studies, participant-level data from multiple studies are often pooled and results are obtained from a single analysis. We consider the impact of differential phenotype variances by study, which we term ‘variance stratification’. Unaccounted for, variance stratification can lead to both decreased statistical power, and increased false positives rates, depending on how allele frequencies, sample sizes, and phenotypic variances vary across the studies that are pooled. We develop a procedure to compute variant-specific inflation factors, and show how it can be used for diagnosis of genetic association analyses on pooled individual level data from multiple studies. We describe a WGS-appropriate analysis approach, implemented in freely-available software, which allows study-specific variances and thereby improves performance in practice. We illustrate the variance stratification problem, its solutions, and the proposed diagnostic procedure, in simulations and in data from the Trans-Omics for Precision Medicine Whole Genome Sequencing Program (TOPMed), used in association tests for hemoglobin concentrations and BMI.