期刊
GENES
卷 11, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/genes11030268
关键词
causality; comorbidity; endometriosis; gene-based association study; genetic overlap; GWAS; Mendelian randomisation; migraine; molecular genetics; pathway enrichment study
资金
- Queensland University of Technology Postgraduate ResearchAwards (QUTPRA)
- National Health and Medical Research Council (NHMRC) of Australia [241,944, 339,462, 443,036, 496,739, 1,026,033, 1,050,208, 389,927, 389,875, 389,891, 389,892, 389,938, 442,915, 442,981, 496,610, 552,485, 552,498]
- Wellcome Trust [WT084766/Z/08/Z]
- Lundbeck Foundation, Denmark [R102-A9118, R155-2014-1724]
- Novo Nordisk Foundation
- Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC)
- Cerylid Biosciences (Melbourne)
- BioBank Japan project - Ministry of Education, Culture, Sports, Sciences and Technology of Japanese government
- Wellcome Trust Case-Control Consortium [076113, 085475]
Observational epidemiological studies indicate that endometriosis and migraine co-occur within individuals more than expected by chance. However, the aetiology and biological mechanisms underlying their comorbidity remain unknown. Here we examined the relationship between endometriosis and migraine using genome-wide association study (GWAS) data. Single nucleotide polymorphism (SNP) effect concordance analysis found a significant concordance of SNP risk effects across endometriosis and migraine GWAS. Linkage disequilibrium score regression analysis found a positive and highly significant genetic correlation (r(G) = 0.38, P = 2.30 x 10(-25)) between endometriosis and migraine. A meta-analysis of endometriosis and migraine GWAS data did not reveal novel genome-wide significant SNPs, and Mendelian randomisation analysis found no evidence for a causal relationship between the two traits. However, gene-based analyses identified two novel loci for migraine. Also, we found significant enrichment of genes nominally associated (P-gene < 0.05) with both traits (Pbinomial-test = 9.83 x 10(-6)). Combining gene-based p-values across endometriosis and migraine, three genes, two (TRIM32 and SLC35G6) of which are at novel loci, were genome-wide significant. Genes having P-gene < 0.1 for both endometriosis and migraine (Pbinomial-test = 1.85 x10(-)degrees (3)) were significantly enriched for biological pathways, including interleukin-1 receptor binding, focal adhesion-PI3K-Akt-mTOR-signaling, MAPK and TNF-alpha signalling. Our findings further confirm the comorbidity of endometriosis and migraine and indicate a non-causal relationship between the two traits, with shared genetically-controlled biological mechanisms underlying the co-occurrence of the two disorders.
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