Large-scale meta-analysis highlights the hypothalamic–pituitary–gonadal axis in the genetic regulation of menstrual cycle length

Laisk, Triin; Kukuškina, Viktorija; Palmer, Duncan S.; Laber, Samantha; Cy, Chen; Ferreira, Teresa; Rahmioğlu, Nilüfer; Zondervan, Krina T.; Becker, Christian M.; Smoller, J. W.; Lippincott, Margaret F.; Salumets, Andres; Granne, Ingrid; Seminara, Stephanie B.; Neale, Benjamin M.; Mägi, Reedik; Lindgren, Cecilia M.

doi:10.1093/hmg/ddy317

Cited by 17 publications

(14 citation statements)

References 56 publications

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“…In males, FSH does not stimulate androgen aromatization but is instead required for sperm production. Consistent with differential roles of FSH, a previously described GWAS hit for menstrual cycle length at FSHB ( Laisk et al, 2018 ) shows suggestive association with testosterone in females but not males ( Supplementary file 6 ).…”

Section: Resultssupporting

confidence: 68%

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GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

Sinnott-Armstrong

Naqvi

Rivas

et al. 2021

eLife

113

159

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Genome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. We describe UK Biobank GWAS results for three molecular traits—urate, IGF-1, and testosterone—with better-understood biology than most other complex traits. We find that many of the most significant hits are readily interpretable. We observe huge enrichment of associations near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of each trait, including differences in testosterone regulation between females and males. At the same time, even these molecular traits are highly polygenic, with many thousands of variants spread across the genome contributing to trait variance. In summary, for these three molecular traits we identify strong enrichment of signal in putative core gene sets, even while most of the SNP-based heritability is driven by a massively polygenic background.

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Section: Resultssupporting

confidence: 68%

“… We observe an association between the previously discovered rs11031006 ( Ruth et al, 2016 ; Laisk et al, 2018 ) and serum testosterone levels in females. This association was reproduced in the non-British White individuals in UK Biobank.…”

Section: Additional Filessupporting

confidence: 48%

GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

Sinnott-Armstrong

Naqvi

Rivas

et al. 2021

eLife

113

159

View full text Add to dashboard Cite

show abstract

“…In males, FSH does not stimulate androgen aromatization but is instead required for sperm production. Consistent with differential roles of FSH, a previously described GWAS hit for menstrual cycle length at FSHB [70] shows suggestive association with testosterone in females but not males (Table S2).…”

Section: Testosteronesupporting

confidence: 70%

GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

Sinnott-Armstrong

Naqvi

Rivas

et al. 2020

Preprint

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Genome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. However, for most traits it remains difficult to interpret what genes and biological processes are impacted by the top hits. Here, as a contrast, we describe UK Biobank GWAS results for three molecular traits-urate, IGF-1, and testosterone-that are biologically simpler than most diseases, and for which we know a great deal in advance about the core genes and pathways. Unlike most GWAS of complex traits, for all three traits we find that most top hits are readily interpretable. We observe huge enrichment of significant signals near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of variation in each trait, including insights into differences in testosterone regulation between females and males. Meanwhile, in other respects the results are reminiscent of GWAS for more-complex traits. In particular, even these molecular traits are highly polygenic, with most of the variance coming not from core genes, but from thousands to tens of thousands of variants spread across most of the genome. Given that diseases are often impacted by many distinct biological processes, including these three, our results help to illustrate why so many variants can affect risk for any given disease.

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“…While a recent genome‐wide meta‐analysis in endometriosis found genetically associated comorbidity with other conditions associated with chronic pain [Rahmioglu et al., preprint, https://doi.org/10.1101/406967]. Additionally, symptoms commonly found in association with chronic pelvic pain have also been shown to be heritable, including: menstrual cycle length [22] and menstrual flow [23]; urinary incontinence, frequency and nocturia [24]; and a genetic contribution to transit time through the gastro‐intestinal tract [25], which may also impact on bowel symptoms.…”

Section: Aetiology and Associationsmentioning

confidence: 99%

An update on the management of chronic pelvic pain in women

Vincent

Evans

2021

Anaesthesia

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Summary Chronic pelvic pain represents a major public health problem for women and impacts significantly on their quality of life. Yet it is under‐researched and a challenge to manage. Women who suffer from chronic pelvic pain frequently describe their healthcare journey as long, via a variety of specialists and frustrating, with their pain often dismissed. Aetiological factors and associations are best conceptualised using the ‘three P’s’ model of predisposing, precipitating and perpetuating factors. This integrates the numerous biological, psychological and social contributors to the complex, multifactorial nature of chronic pelvic pain. Overall management involves analgesia, hormonal therapies, physiotherapy, psychological approaches and lifestyle advice, which like other chronic pain conditions relies on a multidisciplinary team approach delivered by professionals experienced and trained in managing chronic pelvic pain.

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Large-scale meta-analysis highlights the hypothalamic–pituitary–gonadal axis in the genetic regulation of menstrual cycle length

Cited by 17 publications

References 56 publications

GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

An update on the management of chronic pelvic pain in women

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