A variational Bayes discrete mixture test for rare variant association.
Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that "aggregate" tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare-variant test that explicitly models a fraction of variants as neutral, tests associations at the gene-level, and infers the rare-variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome-wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare-variants imputed from the National Heart, Lung, and Blood Institute's Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (~10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans.
Benjamin A
BA
Logsdon
James Y
JY
Dai
Paul L
PL
Auer
Jill M
JM
Johnsen
Santhi K
SK
Ganesh
Nicholas L
NL
Smith
James G
JG
Wilson
Russell P
RP
Tracy
Leslie A
LA
Lange
Shuo
S
Jiao
Stephen S
SS
Rich
Guillaume
G
Lettre
Christopher S
CS
Carlson
Rebecca D
RD
Jackson
Christopher J
CJ
O'Donnell
Mark M
MM
Wurfel
Deborah A
DA
Nickerson
Hua
H
Tang
Alexander P
AP
Reiner
Charles
C
Kooperberg
D001741:Black or African American / Q000235:genetics; D000465:Algorithms; D001499:Bayes Theorem; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020125:Mutation, Missense / Q000235:genetics; D054555:National Heart, Lung, and Blood Institute (U.S.); D010641:Phenotype; D012107:Research Design; D017422:Sequence Analysis, DNA; D012984:Software; D014481:United States; D014841:von Willebrand Factor / Q000032:analysis / Q000235:genetics*
D014841:von Willebrand Factor