Over the past -25 years, we have studied reproductive phenotypes in >500 Hutterite couples. Although our previous focus was on HLA region genes, our studies also suggested that non-HLA genes influencing fertility were also segregating in the population. Thus, in this renewal application, we will continue to study the genetics of fertility in the Hutterites, but now use genome-wide approaches to identify novel genes. We propose to identify and characterize genes that contribute to female and male fertility, measured by the number of births per years of marriage, which are highly heritable traits in the Hutterites (66% heritability in females and 42% heritability in males). An initial genome-wide screen with ~1,500 markers already identified 5 novel genes (1 in females, 4 in males) that met criteria for genome-wide significance. In this application we propose to further characterize 4 of these potential fertility genes in Hutterite couples participating in a prospective study of pregnancy outcome (currently in it's 20th year) and in outbred populations (including women with recurrent pregnancy loss and infertility; and males with nonobstructive azoospermia). In addition, we propose to conduct genome-wide association studies of female and male fertility in the Hutterites using 500,000 SNPs to identify additional fertility genes, and then characterize those genes as well in the Hutterites and in outbred populations. These studies will largely utilize infrastructure (genotypes, phenotypes, computational resources) already available to us. Lastly, we propose to extend our mapping methods to include genes on non-autosomal chromosomes (X, Y, mitochondrial) and study the impact of genes on those chromosomes on fertility in women (X, mitochondrial) and in men (X, Y, mitochondrial). These studies have the potential to identify novel genes and pathways that influence fertility, and possibly infertility, and could lead to improved treatments for infertility or recurrent miscarriage, or to improved methods of contraception. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD021244-22
Application #
7485571
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Taymans, Susan
Project Start
1988-10-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
22
Fiscal Year
2008
Total Cost
$270,774
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Sengupta, Subhajit; Gulukota, Kamalakar; Zhu, Yitan et al. (2016) Ultra-fast local-haplotype variant calling using paired-end DNA-sequencing data reveals somatic mosaicism in tumor and normal blood samples. Nucleic Acids Res 44:e25
Burrows, Courtney K; Kosova, Gülüm; Herman, Catherine et al. (2016) Expression Quantitative Trait Locus Mapping Studies in Mid-secretory Phase Endometrial Cells Identifies HLA-F and TAP2 as Fecundability-Associated Genes. PLoS Genet 12:e1005858
Livne, Oren E; Han, Lide; Alkorta-Aranburu, Gorka et al. (2015) PRIMAL: Fast and accurate pedigree-based imputation from sequence data in a founder population. PLoS Comput Biol 11:e1004139
Gao, Ziyue; Waggoner, Darrel; Stephens, Matthew et al. (2015) An estimate of the average number of recessive lethal mutations carried by humans. Genetics 199:1243-54
Kosova, Gülüm; Stephenson, Mary D; Lynch, Vincent J et al. (2015) Evolutionary forward genomics reveals novel insights into the genes and pathways dysregulated in recurrent early pregnancy loss. Hum Reprod 30:519-29
Campbell, Catarina D; Mohajeri, Kiana; Malig, Maika et al. (2014) Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma. PLoS One 9:e104396
Kosova, Gülüm; Hotaling, James M; Ohlander, Samuel et al. (2014) Variants in DPF3 and DSCAML1 are associated with sperm morphology. J Assist Reprod Genet 31:131-7
Anderson, Rebecca L; Murray, Kathleen; Chong, Jessica X et al. (2014) Disclosure of genetic research results to members of a founder population. J Genet Couns 23:984-91
Bögershausen, Nina; Shahrzad, Nassim; Chong, Jessica X et al. (2013) Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. Am J Hum Genet 93:181-90
Gerull, Brenda; Kirchner, Florian; Chong, Jessica X et al. (2013) Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population. Circ Cardiovasc Genet 6:327-36

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