Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale
Date
2020-09-01Author
Li, XihaoLi, Zilin
Zhou, Hufeng
Gaynor, Sheila M.
Liu, Yaowu
Chen, Han
Sun, Ryan
Dey, Rounak
Arnett, Donna K.
Aslibekyan, Stella
Ballantyne, Christie M.
Bielak, Lawrence F.
Blangero, John
Boerwinkle, Eric
Bowden, Donald W.
Broome, Jai G.
Conomos, Matthew P.
Correa, Adolfo
Cupples, L. Adrienne
Curran, Joanne E.
Freedman, Barry I.
Guo, Xiuqing
Hindy, George
Irvin, Marguerite R.
Kardia, Sharon L.R.
Kathiresan, Sekar
Khan, Alyna T.
Kooperberg, Charles L.
Laurie, Cathy C.
Liu, X. Shirley
Mahaney, Michael C.
Manichaikul, Ani W.
Martin, Lisa W.
Mathias, Rasika A.
McGarvey, Stephen T.
Mitchell, Braxton D.
Montasser, May E.
Moore, Jill E.
Morrison, Alanna C.
O’Connell, Jeffrey R.
Palmer, Nicholette D.
Pampana, Akhil
Peralta, Juan M.
Peyser, Patricia A.
Psaty, Bruce M.
Redline, Susan
Rice, Kenneth M.
Rich, Stephen S.
Smith, Jennifer A.
Tiwari, Hemant K.
Tsai, Michael Y.
Vasan, Ramachandran S.
Wang, Fei Fei
Weeks, Daniel E.
Weng, Zhiping
Wilson, James G.
Yanek, Lisa R.
Abe, Namiko
Abecasis, Gonçalo R.
Aguet, Francois
Albert, Christine
Almasy, Laura
Alonso, Alvaro
Ament, Seth
Anderson, Peter
Anugu, Pramod
Applebaum-Bowden, Deborah
Ardlie, Kristin
Arking, Dan
Ashley-Koch, Allison
Assimes, Tim
Auer, Paul
Avramopoulos, Dimitrios
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
Bis, Joshua
Blackwell, Thomas
Bowler, Russell
Brody, Jennifer
Broeckel, Ulrich
Bunting, Karen
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Metadata
Show full item recordAbstract
Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce ‘annotation principal components’, multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
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