title: Imputation of the rare HOXB13 G84E mutation and cancer risk in a large population-based cohort.
abstract: An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show that by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from Kaiser specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37–0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4x10-12). The G84E mutation was also associated with an increase in risk for the fourteen other most common cancers considered collectively (p = 5.8x10-4) and more so in cases diagnosed with multiple cancer types, both those including and not including prostate cancer, strongly suggesting pleiotropic effects. [corrected].
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors: Thomas J
authors: TJ
authors: Hoffmann
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Lori C
authors: LC
authors: Sakoda
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Ling
authors: L
authors: Shen
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Eric
authors: E
authors: Jorgenson
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Laurel A
authors: LA
authors: Habel
authors: Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors: Jinghua
authors: J
authors: Liu
authors: Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors: Mark N
authors: MN
authors: Kvale
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Maryam M
authors: MM
authors: Asgari
authors: Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors: Yambazi
authors: Y
authors: Banda
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Douglas
authors: D
authors: Corley
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Lawrence H
authors: LH
authors: Kushi
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Charles P
authors: CP
authors: Quesenberry
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Catherine
authors: C
authors: Schaefer
authors: Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America; Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
authors: Stephen K
authors: SK
authors: Van Den Eeden
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America; Division of Research, Kaiser Permanente, Northern California, Oakland, California, United States of America.
authors: Neil
authors: N
authors: Risch
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America; Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
authors: John S
authors: JS
authors: Witte
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002140:California; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors
chemical_list: C484414:HOXB13 protein, human; D018398:Homeodomain Proteins
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