Genome-wide association study of time-to-first-conception in >36,000 women

On average, couples of reproductive age in the United States achieve pregnancy within 6 months of starting timed intercourse, but ∼15% take longer than a year or are unable to conceive. Maternal age is often cited as a major determinant of time to conception; however, other clinical or subclinical factors may also contribute. Uncovering these factors, especially in idiopathic cases, will help drive better reproductive care and outcomes. Identify genetic variants associated with a time to conception longer than 12 months for first pregnancy among women <35 years old. In collaboration with the personal genetics company 23andMe, Inc., we conducted a genome-wide association study (GWAS) in research-consented women of European ancestry. Cases were women who reported trying to conceive for ≥13 months in their first pregnancy attempt (n=9,822). Controls were women with ≥1 biological child who reported trying to conceive for <6 months in their first pregnancy attempt (n=26,947). Samples were genotyped on 1 of 4 versions of a custom, genome-wide genotyping array targeting between 556 and 955K genetic variants. Samples were then imputed for 15M variants using phase I of the 1000 Genomes Project as a reference. Assuming an additive model, we tested logistic regression on the time-to-first-conception phenotype, including age, first 5 principal components, and genotyping array version as covariates. We utilized an in-house database developed for this purpose to annotate the reproductive biological functions of the variants in linkage disequilibrium with the index SNP and proximal genes within the statistically significant loci. Two genomic loci reached genome-wide significance (p<5×10−8) with trying to conceive a first pregnancy for ≥13 months. Variant rs61768001, in the WNT4 gene, was the most strongly associated variant in the first locus (p=4.6×10−10, OR=1.16). WNT4 has been linked to regulation of both uterine embryonic development and postnatal uterine biology. For example, rare missense variants within WNT4 have been found in patients with Müllerian aplasia [1]. WNT4 may also regulate human endometrial decidualization [2], and deletion of Wnt4 in the mouse uterus compromises embryo implantation and causes subfertility [3]. The WNT4 locus has also been associated with endometriosis in published GWAS [4-8]. The most strongly associated variant in the second locus, rs11031006 (p=3.6×10−8, OR=1.14), is ∼25 kb upstream of FSHB, which encodes the β-subunit of follicle stimulating hormone (FSH). The variant rs10835638 in the FSHB promoter, included in the credible SNP set in our analysis, has been associated with reduced FSH serum levels, PCOS diagnosis, longer menstrual cycles, increased age of menopause, and higher rates of female nulliparity [9]. By contrast, the rs11031006-G allele, which was associated with conception in <6 months in our analysis, has been associated with earlier age at menarche, first live birth, and menopause, but also higher dizygotic twinning rates and higher lifetime parity [10]. Our results suggest that genetic variants in mechanisms regulating uterine development, endometrial function, and/or gonadotropin signaling influence the time to first conception. Further investigation will reveal the specific biological processes responsible for the phenotype.