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.
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