Genome-wide Association Analysis Of Primary Dysmenorrhea And Its Genetic Overlap With Years Of Schooling And Other Complex Traits

BackgroundPrimary dysmenorrhea（PDM）is a common gynecological disease that occurs during menstruation or premenstrual period and is characterized by chronic spastic pain in the lower abdomen without organic pathological changes.In severe cases,it affects the quality of life of adolescent and childbearing women.The occurrence of PDM is jointly affected by environmental and genetic factors,but the current research on the genetic risk factors of PDM is limited.In this study,a genome-wide association study（GWAS）was used to study the genetic susceptibility of polygenic complex traits of PDM.In addition,this study further revealed the association between PDM and other complex traits by using global and local genetic correlation analysis and Mendelian Randomization（MR）,providing new entry point insights for in-depth understanding of the genetic structural basis and risk factors of PDM.MethodsA total of 14,452 participants from Europe and China were selected for this study.European samples were obtained from the UK Biobank（UKB）using ICD9 and 10 to screen for PDM;Chinese samples were obtained from the We Gene cohort and Bio-X cohort using questionnaires and routine physical examination to obtain PDM cases,respectively.All participants signed an informed consent form.UKB and Bio-X samples were preprocessed and standardized for genotype data analysis using the RICOPILI analysis pipeline.The genotype data from the We Gene cohort were quality-controlled,then phasing and imputation were performed using Eagle2 and Minimac4,respectively,and PLINK1.9software for case-control analysis to find genetic variants associated with PDM.Subsequently,cross-ethnic meta-analysis was performed on data from European and Chinese populations.Popcorn software was used to conduct cross-ethnic correlation analysis between European and Chinese populations to explore the degree of sharing of PDM-related genetic variants in different ethnic populations.Genetic overlap studies were performed using publicly available GWAS summary statistics and genetic correlation analysis using LDSC software,followed by SUPERGNOVA software to determine the local genetic correlations of complex traits associated with PDM to identify possible shared genetic regions,and finally,six MR analysis methods were used to further determine whether the common genetic effects between PDM and related traits have a causal relationship.ResultsA total of 6,465 Europeans（2,349 PDM vs 4,116 Control,age:40-69 years）and 7,987Chinese（4,289 PDM vs 3,698 Control,age:13-68 years）were included in the GWAS study.In the European population,the most strongly associated locus with PDM was rs12568462(P=1.59×10^-6,OR=1.22)but not to genome-wide significant levels.In the Chinese population and cross-ethnic meta-analysis,rs11676014(P_CHN=2.44×10^-13,P_Meta=5.20×10^-12)within the IL1A and IL1B region and independent rs2068797(P_Meta=1.16×10^-10)and rs2982742(P_CHN=1.91×10^-13)within the NGF region reached genome-wide significant levels.In genetic correlation analysis,PDM had significant genetic overlap with years of schooling(SNP-rg±se=-0.71±0.14;P=2.10×10^-7),college completion(-0.85±0.21;P=5.13×10^-5),cognitive performance(-0.85±0.19;P=1.38×10^-5),attention deficit hyperactivity disorder(ADHD,0.68±0.16;P=2.11×10^-5),major depression(MDD,0.47±0.11;P=3.02×10^-5),waist-to-hip ratio(WHR,0.41±0.11;P=1.31×10^-4),waist circumference(0.36±0.10;P=2.82×10^-4),and age at first birth(AFB,-0.64±0.14;P=7.88×10^-6).Among the 2,239 genomic regions,there were two significant local genetic correlation regions between PDM and years of schooling(chr14:22738161-23607730,P=2.08×10^-9;chr19:18506815-19873269,P=2.28×10^-6),and one significant local genetic correlation regions between college completion(chr1:169078572-169521853,P=9.71×10^-7).In MR analysis,the causal association between years of schooling and PDM was consistent in multiple models(P_WM=4.08×10^-5,P_IVW=1.35×10^-11,P_GSMR=1.98×10^-11,P_MR-PRESSO=6.82×10^-13,P_CAUSE=2.70×10^-2).ConclusionsIn summary,the present study validated previously reported genetic susceptibility loci in the 1p13.2 and 2q13 regions associated with PDM in Chinese,European,and cross-ethnic populations.Furthermore,genetic overlap analysis revealed significant correlations between PDM and educational attainment,cognitive performance,psychiatry,reproductive traits,and anthropometric characteristics,where years of schooling causally associated with PDM,while genetic correlations for other phenotypes may be due to genetic pleiotropy.