Gordon, S. D. | bioRxiv Science

bioRxiv2018

Genome-wide association analysis identifies 27 novel loci associated with uterine leiomyomata revealing common genetic origins with endometriosis

Uterine leiomyomata (UL), also known as uterine fibroids, are the most common neoplasms of the reproductive tract and the primary cause for hysterectomy, leading to considerable impact on womens lives as well as high economic burden1,2. Genetic epidemiologic studies indicate that heritable risk factors contribute to UL pathogenesis3. Previous genome-wide association studies (GWAS) identified five loci associated with UL at genome-wide significance (P < 5 x 10-8)4-6. We conducted GWAS meta-analysis in 20,406 cases and 223,918 female controls of white European ancestry, identifying 24 genome-wide significant independent loci; 17 replicated in an unrelated cohort of 15,068 additional cases and 43,587 female controls. Aggregation of discovery and replication studies (35,474 cases and 267,505 female controls) revealed six additional significant loci. Interestingly, four of the 17 loci identified and replicated in these analyses have also been associated with risk for endometriosis - another common gynecologic disorder. These findings increase our understanding of the biological mechanisms underlying UL development, and suggest overlapping genetic origins with endometriosis.

genomics↗

bioRxiv2018

Bivariate genome-wide association analysis strengthens the role of bitter receptor clusters on chromosomes 7 and 12 in human bitter taste

Human perception of bitter substances is partially genetically determined. Previously we discovered a single nucleotide polymorphism (SNP) within the bitter taste receptor gene TAS2R19 on chromosome 12 that accounts for 5.8% of the variance in the perceived intensity rating of quinine, and we strengthened the classic association between TAS2R38 genotype and the bitterness of propylthiouracil (PROP). Here we performed a genome-wide association study (GWAS) using a 40% larger sample (n = 1999) together with a bivariate approach to detect previously unidentified common variants with small effects on bitter perception. We identified two signals, both with small effects (< 2%), within the bitter taste receptor clusters on chromosomes 7 and 12, which influence the perceived bitterness of denatonium benzoate and sucrose octaacetate respectively. We also provided the first independent replication for an association of caffeine bitterness on chromosome 12. Furthermore, we provided evidence for pleiotropic effects on quinine, caffeine, sucrose octaacetate and denatonium benzoate for the three SNPs on chromosome 12 and the functional importance of the SNPs for denatonium benzoate bitterness. These findings provide new insights into the genetic architecture of bitter taste and offer a useful starting point for determining the biological pathways linking perception of bitter substances.

genetics↗