A genome-wide association study of female sexual dysfunction

Abstract

Background: Female sexual dysfunction (FSD) is an important but controversial problem with serious negative impact on women's quality of life. Data from twin studies have shown a genetic contribution to the development and maintenance of FSD.

Methodology/principal findings: We performed a genome-wide association study (GWAS) on 2.5 million single-nucleotide polymorphisms (SNPs) in 1,104 female twins (25-81 years of age) in a population-based register and phenotypic data on lifelong sexual functioning. Although none reached conventional genome-wide level of significance (10 × -8), we found strongly suggestive associations with the phenotypic dimension of arousal (rs13202860, P = 1.2 × 10(-7); rs1876525, P = 1.2 × 10(-7); and rs13209281 P = 8.3 × 10(-7)) on chromosome 6, around 500 kb upstream of the locus HTR1E (5-hydroxytryptamine receptor 1E) locus, related to the serotonin brain pathways. We could not replicate previously reported candidate SNPs associated with FSD in the DRD4, 5HT2A and IL-1B loci.

Conclusions/significance: We report the first GWAS of FSD symptoms in humans. This has pointed to several "risk alleles" and the implication of the serotonin and GABA pathways. Ultimately, understanding key mechanisms via this research may lead to new FSD treatments and inform clinical practice and developments in psychiatric nosology.

Figure 1. Manhattan plots describing the association of 2.5 M SNPs with sexual arousal, lubrication and overall sexual functioning.

SNPs with P≤10–6 are highlighted with a red circle (n = 1104 females).

Figure 2. Association scatter plot for SNPs in the gene desert approximately 1Mbp upstream of the HTR1E gene.

TwinsUK discovery cohort. Negative logarithms of the P values for the association of each SNP with spherical equivalence are plotted. The lead SNP is plotted in diamond shape, with the GWAS-analysis P value for that SNP indicated. Genotyped SNPs are plotted as squares, with the colour indicating the degree of pairwise LD between the lead and neighbouring SNPs. Red indicates strong pairwise LD, with r2≥0.8; orange indicates moderate LD, with 0.5

Figure 3. Haploview LD plot. The plot uses the hapmapPhase3 data on the CEU and the TSI Caucasian populations and encompasses an 800 kbp segment containing the associated SNP on chromosome 6 and HTR1E.

The LD blocks were defined by confidence intervals according to Gabriel and colleagues . The x-axis corresponds to the genomic position in kb and the red triangles defined by black lines represent LD blocks. The yellow arrow and the red box indicate the location of three GWAS associated SNP and the position of HTR1E, respectively.