Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

Abstract

Background: Polycystic ovary syndrome (PCOS) is a common, complex disorder, which should be recognized as a prominent health concern also outside the context of fertility. Although PCOS affects up to 18% of women worldwide, its etiology remains poorly understood. It is likely that a combination of genetic and environmental factors contributes to the risk of PCOS development. Whilst previous genome-wide association studies have mapped several loci associated with PCOS, analysis of populations with unique population history and genetic makeup has the potential to uncover new low frequency variants with larger effects. In this study, we leverage genetic information of two neighboring and well-characterized populations in Europe - Finnish and Estonian - to provide a basis for a new understanding of the genetic determinants of PCOS. Methods and Findings: We conducted a three-stage case-control genome-wide association study (GWAS). In the discovery phase, we performed a GWAS comprising of a total of 797 cases and 140,558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2,812 cases and 89,230 controls. Finally, we conducted a joint meta-analysis of 3,609 cases and 229,788 controls from both cohorts. In total, we identified three novel genome-wide significant variants associating with PCOS. Two of these novel variants, rs145598156 (p=3.6 x 10-8, OR=3.01 [2.02-4.50] MAF=0.005) and rs182075939 (p=1.9 x 10-16, OR= 1.69 [1.49-1.91], MAF=0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2= 0.95) and a missense I157T (r2=0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, p= 1.7 x 10-8, OR=1.16 (1.10-1.23), MAF=0.44). We also replicated four previous reported associations near the genes ERBB4, DENND1A, FSHB and ZBTB16. Conclusions: We identified three novel variants for PCOS in a Finnish-Estonian GWAS. Using isolated populations to perform genetic association studies provides a useful resource to identify rare variants contributing to the genetic landscape of complex diseases such as PCOS.

Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy

“…Such homogenous populations might facilitate the discovery of rare variants with larger effects and characterization of the genetic basis of complex diseases such as preeclampsia. 57,58 The associations previously reported by Steinthorsdottir et al 11 are similar in effect directions to those now discovered in the preeclampsia phenotype in the Finnish and Estonian cohorts, suggesting that similar genetic background may contribute to preeclampsia in other populations as well.…”

Sex Hormone Candidate Gene Polymorphisms Are Associated with Endometriosis

“…According to previous GWAS data, and analyzed in the present study, the FSHB promoter polymorphisms (rs11031002 and rs11031005) were associated with multiple female reproductive outcomes. For rs11031002, these include LH level (beta = 0.221 for allele A) [16]; serum levels of protein CGA; FSHB (beta = −0.162 for allele A) [19]; polycystic ovary syndrome (PCOS) (OR = 1.24 for allele A) [20]; and bone mineral density (beta = 0.02 for allele T) [21]. For SNP rs11031005, the previous GWAS demonstrated a correlation with both endometriosis and migraine (OR = 1.08 for allele T) [5]; FSH concentration (beta = −0.232 for allele C) [16]; testosterone levels-total (beta = 0.033 for allele C) and bioavailable (beta = 0.023 for allele C) [17]; age at menarche (beta = −0.035 for allele T) [22] and age at menopause [23], PCOS (beta = −0.159 for allele T) [24]; and ovarian cyst (beta = −0.110 for allele C) [25].…”

Fetal genome predicted birth weight and polycystic ovary syndrome in later life: a Mendelian randomization study

“…The allele-specific effects of maternally transmitted or non-transmitted on birth weight were used to represent the maternal and fetal genetic effects, respectively (37). Finally, five maternally transmitted and three maternally nontransmitted SNPs that reached a genome-wide significant level on birth weight were identified from the GWAS by Juliusdottir et al (30) Furthermore, we extracted SNP-POCS associations for each genetic instrument from two independent PCOS GWASs conducted by Day et al and Tyrmi et al,respectively (4,33). If a certain instrument was not available in the summary data, a proxy SNP in high LD in the European population was identified using LDlink (https://ldlink.nci.nih.gov/?tab=ldproxy).…”

“…A secondary MR analysis was conducted using the fetal genetic associations extracted from the birth weight GWAS by Warrington et al (29), after excluding maternally transmitted or nontransmitted alleles that were identified in the GWAS by Juliusdottir et al (30) In addition, to validate the causal estimates in the primary MR analysis, a replication MR analysis was performed using data from an independent PCOS GWAS metaanalysis in the FinnGen and EstBB (33). To increase the statistical power and precision of causal estimates, a fixed-effect meta-analysis was conducted to pool the IVW estimates from the primary/ secondary and replication analyses.…”