Heterozygosity mapping for human dominant trait variants.

TitleHeterozygosity mapping for human dominant trait variants.
Publication TypeJournal Article
Year of Publication2019
AuthorsImai-Okazaki, A, Li, Y, Horpaopan, S, Riazalhosseini, Y, Garshasbi, M, Mosse, YP, Zhang, D, Schrauwen, I, Sharma, A, Fann, CSJ, Leal, SM, Lathrop, M, Ott, J
JournalHum Mutat
Date Published2019 Apr 24

Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. We confirm existence of this phenomenon in sequence data with known dominant pathogenic variants obtained on family members and in unrelated population controls. A computer-based approach to estimating empirical significance levels associated with our test statistics shows genome-wide p-values smaller than 0.05 for many but not all of the individuals carrying a pathogenic variant.

Alternate JournalHum. Mutat.
PubMed ID31018026
Grant List102215/2/13/2 / / Wellcome /
DC003594 / / National Institutes of Health /
MOST 106-2314-B-001-004-MY2 / / Taiwan Minister of Science and Technology /
/ / U.S. National Institutes of Health /
/ / Japan Society for the Promotion of Science (JSPS) KAKENHI /
/ / UK Medical Research Council /
DC011651 / / National Institutes of Health /
R01 HG008972 / HG / NHGRI NIH HHS / United States
project grants 3150 1002 / / NSFC China /
UM1 HG006493 / HG / NHGRI NIH HHS / United States
KAKENHI grant number JP18K15863 / / Japan Society for the Promotion of Science (JSPS) /
KAKENHI Grant Number JP16K19404 / / Japan Society for the Promotion of Science (JSPS) /
/ / University of Bristol /
project grant 3147 0070 / / NSFC China /