title: Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus.
abstract: Dysmenorrhea is a common chronic pelvic pain syndrome affecting women of childbearing potential. Family studies suggest that genetic background influences the severity of dysmenorrhea, but genetic predisposition and molecular mechanisms underlying dysmenorrhea are not understood. In this study, we conduct the first genome-wide association study to identify genetic factors associated with dysmenorrhea pain severity. A cohort of females of European descent (n = 11,891) aged 18 to 45 years rated their average dysmenorrhea pain severity. We used a linear regression model adjusting for age and body mass index, identifying one genome-wide significant (P < 5 × 10) association (rs7523086, P = 4.1 × 10, effect size 0.1 [95% confidence interval, 0.074-0.126]). This single nucleotide polymorphism is colocalising with NGF, encoding nerve growth factor. The presence of one risk allele corresponds to a predicted 0.1-point increase in pain intensity on a 4-point ordinal pain scale. The putative effects on NGF function and/or expression remain unknown. However, genetic variation colocalises with active epigenetic marks in fat and ovary tissues, and expression levels in aorta tissue of a noncoding RNA flanking NGF correlate. Participants reporting extreme dysmenorrhea pain were more likely to report being positive for endometriosis, polycystic ovarian syndrome, depression, and other psychiatric disorders. Our results indicate that dysmenorrhea pain severity is partly genetically determined. NGF already has an established role in chronic pain disorders, and our findings suggest that NGF may be an important mediator for gynaecological/pelvic pain in the viscera.
authors.affiliation: Human Genetics and Computational Biomedicine, Pfizer WRD, Cambridge, United Kingdom.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Jones
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd, Cambridge, United Kingdom.
authors.forename: James R F
authors.initials: JRF
authors.lastname: Hockley
authors.affiliation: Research Statistics, Pfizer WRD, Groton, CT, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Hyde
authors.affiliation: Research Statistics, Pfizer WRD, Pfizer Ltd, Cambridge, United Kingdom.
authors.forename: Donal
authors.initials: D
authors.lastname: Gorman
authors.affiliation: Human Genetics and Computational Biomedicine, Pfizer WRD, Cambridge, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Sredic-Rhodes
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd, Cambridge, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Bilsland
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd, Cambridge, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: McMurray
authors.affiliation: 23andMe, Inc, Mountain View, CA, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Furlotte
authors.affiliation: 23andMe, Inc, Mountain View, CA, USA.
authors.forename: Youna
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 23andMe, Inc, Mountain View, CA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hinds
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd, Cambridge, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cox
authors.affiliation: Human Genetics and Computational Biomedicine, Pfizer WRD, Cambridge, United Kingdom.
authors.forename: Serena
authors.initials: S
authors.lastname: Scollen
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D015331:Cohort Studies; D004412:Dysmenorrhea / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D010147:Pain Measurement; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: C502240:NGF protein, human; D020932:Nerve Growth Factor