title: Genome-Wide Association Study of Meiotic Recombination Phenotypes.
abstract: Meiotic recombination is an essential step in gametogenesis, and is one that also generates genetic diversity. Genome-wide association studies (GWAS) and molecular studies have identified genes that influence of human meiotic recombination. RNF212 is associated with total or average number of recombination events, and PRDM9 is associated with the locations of hotspots, or sequences where crossing over appears to cluster. In addition, a common inversion on chromosome 17 is strongly associated with recombination. Other genes have been identified by GWAS, but those results have not been replicated. In this study, using new datasets, we characterized additional recombination phenotypes to uncover novel candidates and further dissect the role of already known loci. We used three datasets totaling 1562 two-generation families, including 3108 parents with 4304 children. We estimated five different recombination phenotypes including two novel phenotypes (average recombination counts within recombination hotspots and outside of hotspots) using dense SNP array genotype data. We then performed gender-specific and combined-sex genome-wide association studies (GWAS) meta-analyses. We replicated associations for several previously reported recombination genes, including RNF212 and PRDM9 By looking specifically at recombination events outside of hotspots, we showed for the first time that PRDM9 has different effects in males and females. We identified several new candidate loci, particularly for recombination events outside of hotspots. These include regions near the genes SPINK6, EVC2, ARHGAP25, and DLGAP2 This study expands our understanding of human meiotic recombination by characterizing additional features that vary across individuals, and identifying regulatory variants influencing the numbers and locations of recombination events.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 fbegum1@jhu.edu.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Ferdouse
authors.identifier: 0000-0001-7835-8051
authors.initials: F
authors.lastname: Begum
authors.affiliation: Department of Neurology, University of California, Los Angeles, California 90095.
authors.forename: Reshmi
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Vivian G
authors.identifier: 0000-0002-4029-6243
authors.initials: VG
authors.lastname: Cheung
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Stephanie L
authors.identifier: 0000-0003-1789-0479
authors.initials: SL
authors.lastname: Sherman
authors.affiliation: Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261.|Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261.
authors.forename: Eleanor
authors.identifier: 0000-0003-2898-6484
authors.initials: E
authors.lastname: Feingold
mesh_terms: D003434:Crossing Over, Genetic; D004261:DNA Replication; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D008025:Ligases / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics*; D059372:Nucleotide Motifs; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D012737:Sex Factors
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human; D008025:Ligases; C527435:RNF212 protein, human
keywords: GWAS meta-analysis; average recombination; crossover; hotspot/nonhotspot; nondisjunction