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Meta-Analysis
. 2024 Feb 26;25(1):208.
doi: 10.1186/s12864-024-09990-w.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

Kharis Burns  1   2 , Benjamin H Mullin  3   4 , Loes M E Moolhuijsen  5 , Triin Laisk  6 , Jaakko S Tyrmi  7   8 , Jinrui Cui  9 , Ky'Era V Actkins  10   11   12 , Yvonne V Louwers  13 ; Estonian Biobank Research Team; Lea K Davis  11   12 , Frank Dudbridge  14 , Ricardo Azziz  15 , Mark O Goodarzi  9 , Hannele Laivuori  7   16   17   18 , Reedik Mägi  6 , Jenny A Visser  5 , Joop S E Laven  13 , Scott G Wilson  3   4   19 ; FinnGen; International PCOS Consortium; Felix R Day  20 , Bronwyn G A Stuckey  21   3   22
Collaborators, Affiliations
Meta-Analysis

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

Kharis Burns et al. BMC Genomics. .

Abstract

Background: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes.

Results: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata.

Conclusions: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Keywords: BMI; Body mass index; GWAS; Lean; Meta-analysis; Obese; PCOS; Polycystic ovary syndrome.

PubMed Disclaimer

Conflict of interest statement

The FinnGen project is funded by the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sarl), Genentech Inc., Merck Sharp & Dohme Corp., Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH. All other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Regional association plots of genome-wide significant loci identified in the lean PCOS meta-analysis. A 9q33.3 (DENND1A) and B 22q12.1 (XBP1). Genetic variants are depicted by position (x-axis) together with their meta-analysis P-value (-log10; y-axis). Variants are colour coded according to their LD (r2) with the lead variant. Mb = million bases
Fig. 2
Fig. 2
Graph of lead variants in the meta-analyses showing at least suggestive association from each locus. A P-values are shown from the meta-analyses of the lean PCOS strata (x-axis) or the combined overweight/obese PCOS strata (y-axis). Blue symbols show lead variants with at least suggestive association (P < 5 × 10–6) in the lean PCOS strata, red symbols show variants with at least suggestive association in the combined overweight/obese PCOS strata and green variants are those with at least suggestive association in both lean PCOS and combined overweight/obese PCOS strata. Lead variants that did not achieve suggestive association fall in the grey region. Dashed lines show the threshold for genome-wide suggestive association (P < 5 × 10–6). B Plot of the effect size (beta ± SE) for the risk allele of lead variants showing at least suggestive association in the lean PCOS strata (blue symbols), combined overweight/obese PCOS strata (red) and variants that show at least suggestive association in both the lean PCOS and combined overweight/obese PCOS strata (green). Dashed line shows the diagonal
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