Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality

Adewuyi, Emmanuel O; Mehta, Divya; Sapkota, Yadav; Auta, Asa; Yoshihara, Kosuke; Nyegaard, Mette; Griffiths, Lyn R.; Montgomery, Grant W.; Chasman, Daniel I.; Nyholt, Dale R.

doi:10.1007/s00439-020-02223-6

Cited by 48 publications

(77 citation statements)

References 130 publications

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“…Taken together, evidence suggests comorbidity between AD and GIT disorders, although it is not clear whether GIT traits are risks for AD or vice versa. Regardless, these findings agree with the concept of the 'gut-brain' axis or the 'gastric mucosa-brain' relationship, which has been implicated in the association between GIT-related traits and central nervous system (CNS) disorders including depression and Parkinson's disease [13][14][15][16] . In support of a possible link between AD and GIT traits, a recent animal model-based study indicates that intragastrointestinal accumulation of Ab may induce gastric function alteration, CNS amyloidosis, and subsequent AD-like dementia 17 .…”

Section: Introductionsupporting

confidence: 83%

Cross–trait analysis of Alzheimer’s disease and gastrointestinal tract disorders identifies shared loci highlighting immune-related and statin pathways

Adewuyi¹,

O’Brien²,

Nyholt³

et al. 2021

Preprint

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Several observational studies suggest a relationship between Alzheimer’s disease (AD) and gastrointestinal tract (GIT) disorders; however, their underlying mechanisms remain unclear. Here, we analysed several genome-wide association studies (GWAS) summary statistics (N = 34,652 – 456,327) to assess AD and GIT disorders relationships. We found a significant genetic overlap and correlation between AD and each of gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), medications for GERD or PUD (PGM), gastritis-duodenitis, irritable bowel syndrome and diverticulosis, but not inflammatory bowel disease. Our analysis suggests a partial causal association between AD and gastritis-duodenitis, diverticulosis and medication for PUD. GWAS meta-analysis identified seven loci (P < 5 × 10-8, PDE4B, CD46, SEMA3F, HLA-DRA, MTSS2, PHB, and APOE) shared by AD and PGM, six of which are novel. These loci were replicated using GERD and PUD GWAS and reinforced in gene-based analyses. Lipid metabolism, autoimmune system, lipase inhibitors, PD-1 signalling, and statin pathways were significantly enriched for AD and GIT disorders. These findings support shared genetic susceptibility in AD and GIT disorders. Lipase inhibitors and statins may provide novel therapeutic avenues for AD, GIT disorders, or their comorbidity.

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Section: Introductionsupporting

confidence: 83%

Cross–trait analysis of Alzheimer’s disease and gastrointestinal tract disorders identifies shared loci highlighting immune-related and statin pathways

Adewuyi¹,

O’Brien²,

Nyholt³

et al. 2021

Preprint

Self Cite

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show abstract

“…In the case of migraine there is already discussion surrounding repurposing of drugs used to treat migraine for treatment of endometriosis-associated pain (Saunders and Horne, 2021). Likewise reports that GWAS analysis of datasets related to depression and comparison to those of endometriosis identified a link to 'gastric mucosa abnormality' (Adewuyi et al, 2021) may provide a link to evidence that the gut-brain axis can play a role in pain pathways (Muller et al, 2020) and invigorate studies on dietary modification as a non-drug therapy for both conditions.…”

Section: Have Genomic Studies Provided Any New Diagnostic or Therapeutic Insights?mentioning

confidence: 99%

“…Depression and fatigue are symptoms commonly reported by women with endometriosis (Saunders and Horne, 2021). A meta-analysis of endometriosis and depression GWAS (sample size 709,111), identified 20 independent genome-wide significant loci of which eight were novel (Adewuyi et al, 2021). Genes overlapping the two traits were significantly enriched for the biological pathways 'cell-cell adhesion', 'inositol phosphate metabolism', 'Hippo-Merlin signaling dysregulation' and 'gastric mucosa abnormality'.…”

Section: Genomic Studies Have Revealed Links Between Endometriosis Reproductive Traits and Other Disordersmentioning

confidence: 99%

Insights Gained from Genomic Studies on the Role of Sex Steroids in the Aetiology of Endometriosis

Saunders¹

2021

Preprint

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Endometriosis is a chronic neuro-inflammatory disorder the defining feature of which is the growth of tissue (lesions) that resembles the endometrium in sites outside the uterus. Estimates of prevalence typically quote rates of ~10% of women of reproductive age, equating to ~190 million women world-wide. Three subtypes of endometriosis are usually considered when discussing the aetiology of the disorder - superficial peritoneal, ovarian (endometrioma cysts), and deep (infiltrating). Genetic, hormonal and immunological factors have all been proposed as contributing to risk factors associated with the development of lesions. Twin studies report the heritable component of endometriosis as ~50%. Genome wide association studies (GWAS) have been conducted allowing unbiased scanning of the genome for single nucleotide polymorphisms (SNPs) in many thousands of individuals. These studies have identified SNPs that appear over-represented in patients with endometriosis, particularly those with more extensive disease (stage III/IV). Amongst the larger scale GWAS there has been replication of SNPs near genes involved in oestrogen and other signalling pathways including ESR1 (oestrogen receptor alpha), GREB1, HOXA10, WNT4 and MAPK kinase signalling. The results from patients with endometriosis have also provided an opportunity to make comparisons with GWAS conducted on other patient cohorts including those with reproductive traits (age at menarche) and disorders (fibroids, endometrial and ovarian cancer) and conditions that are reported by women with endometriosis (migraine, depression). These comparative studies have highlighted some shared genetically-controlled biological mechanisms, including hormone-regulated pathways which might explain the co-occurrence of endometriosis with these disorders. In summary, unbiased genetic analysis has provided new insights into the genetic factors that may contribute to increased risk of developing endometriosis. New studies are needed to broaden the range of patients contributing to these datasets and to improve integration with non-genomic and tissue expression data before their full potential for diagnosis and improvements in patient care can be fully realised.

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“…Other pathways and cellular regulators highlighted as a result of genomic studies include the MAP kinase signaling cascade (Uimari et al, 2017), interleukin 1A (a cytokine implicated in inflammatory responses) (Sapkota et al, 2015), WNT signaling (Gallagher et al, 2019), and steroid metabolism (Sapkota et al, 2017). Meta-analysis has also identified shared genetic signatures between migraine and depression with the latter highlighting a link to disturbances in gut mucosa (Adewuyi et al, 2020(Adewuyi et al, , 2021.…”

Section: Genetic and Genomic Impactsmentioning

confidence: 99%

Endometriosis: Etiology, pathobiology, and therapeutic prospects

Saunders

Horne

2021

Cell

388

305

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Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality

Abstract: For more information about UCLan's research in this area go to http://www.uclan.ac.uk/researchgroups/ and search for .

Cited by 48 publications

References 130 publications

Cross–trait analysis of Alzheimer’s disease and gastrointestinal tract disorders identifies shared loci highlighting immune-related and statin pathways

Cross–trait analysis of Alzheimer’s disease and gastrointestinal tract disorders identifies shared loci highlighting immune-related and statin pathways

Insights Gained from Genomic Studies on the Role of Sex Steroids in the Aetiology of Endometriosis

Endometriosis: Etiology, pathobiology, and therapeutic prospects

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