Faculty Collaboration Database

Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men. Hum Mol Genet 2015 Oct 01;24(19):5628-36

Date

07/23/2015

Pubmed ID

26199320

Pubmed Central ID

PMC4902876

DOI

10.1093/hmg/ddv257

Scopus ID

2-s2.0-84943755037 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

Genome-wide association studies (GWAS) have identified several common loci contributing to non-obstructive azoospermia (NOA). However, a substantial fraction of NOA heritability remains undefined, especially those low-frequency [defined here as having a minor allele frequency (MAF) between 0.5 and 5%] and rare (MAF below 0.5%) variants. Here, we performed a 3-stage exome-wide association study in Han Chinese men to evaluate the role of low-frequency or rare germline variants in NOA development. The discovery stage included 962 NOA cases and 1348 healthy male controls genotyped by exome chips and was followed by a 2-stage replication with an additional 2168 cases and 5248 controls. We identified three low-frequency variants located at 6p22.2 (rs2298090 in HIST1H1E encoding p.Lys152Arg: OR = 0.30, P = 2.40 × 10(-16)) and 6p21.33 (rs200847762 in FKBPL encoding p.Pro137Leu: OR = 0.11, P = 3.77 × 10(-16); rs11754464 in MSH5: OR = 1.78, P = 3.71 × 10(-7)) associated with NOA risk after Bonferroni correction. In summary, we report an instance of newly identified signals for NOA risk in genes previously undetected through GWAS on 6p22.2-6p21.33 in a Chinese population and highlight the role of low-frequency variants with a large effect in the process of spermatogenesis.

Author List

Ni B, Lin Y, Sun L, Zhu M, Li Z, Wang H, Yu J, Guo X, Zuo X, Dong J, Xia Y, Wen Y, Wu H, Li H, Zhu Y, Ping P, Chen X, Dai J, Jiang Y, Xu P, Du Q, Yao B, Weng N, Lu H, Wang Z, Zhu X, Yang X, Xiong C, Ma H, Jin G, Xu J, Wang X, Zhou Z, Liu J, Zhang X, Conrad DF, Hu Z, Sha J

Author

Jing Dong PhD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Azoospermia
China
Chromosomes, Human, Pair 6
Exome
Genetic Predisposition to Disease
Genome-Wide Association Study
Germ-Line Mutation
Humans
Male
Polymorphism, Single Nucleotide