Geneetiline varieeruvus kui naisepoolse viljatuse eelsoodumuse mõjutaja ja võimalike uute biomarkerite allikas

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Üks tark mees on öelnud, et lapse saamine on üks ebatõenäoline protsess, ja arvestades seda, kui paljud paarid on viljatusega hädas, oli tal ilmselt õigus. Eestis on enamik naisepoolse viljatuse juhtudest tingitud peamiselt infektsioonide põhjustatud munajuhaviljatusest ja polütsüstiliste munasarjade sündroomist (PCOS), millele on iseloomulik meessuguhormoonide kõrgenenud tase ja insuliinresistentsus. Kunstlik viljastamine võib aidata sellistel juhtudel järglasi saada, kuid kahjuks on ravi tulemuslikkus ~30% ja sõltub suuresti sellest, kuidas munasarjad reageerivad ravi käigus kasutatavatele hormoonidele. Viljatuse molekulaarseid tagamaid on aastate jooksul palju uuritud ja on jõutud järeldusele, et individuaalne geneetiline varieeruvus mängib selle tekkes kindlasti olulist rolli. Geneetilise varieeruvuse uuringud võimaldavad leida ka biomarkereid, mis sobiksid reproduktiivpotentsiaali ja ehk isegi viljatusravi tulemuslikkuse ennustamiseks. Käesoleva töö üldine eesmärk oli hinnata seoseid erinevate geneetiliste variatsioonide ja PCOS-i ning munajuhaviljatuse vahel. Lisaks uurisime mitmeid menopausi algusajaga või munasarja funktsiooniga seotud geneetilisi variante, mis võiksid olla seotud reproduktiivpotentsiaali ja viljatusravi tulemuslikkuse parameetritega. Selle jaoks koguti tervete ja viljakusprobleemidega naiste DNA proovid ning analüüsiti 47 geneetilise variandi seost huvipakkuvate diagnooside ja kliiniliste tunnustega. Et teha kindlaks, kui suur osa munajuhaviljatuse juhtudest on tingitud urogenitaalsest klamüüdiainfektsioonist, määrati munajuhaviljatusega naiste vereseerumist klamüüdia-vastaste antikehade esinemine. Leidsime, et ~50% kõigist munajuhaviljatuse juhtudest võivad olla tingitud eelnevast klamüüdiainfektsioonist ja näitasime, et immuunvastust mõjutav mannoosi siduva lektiini geeni varieeruvus on ilmselt seotud munajuhaviljatuse geneetilise eelsoodumusega. Insuliini ja androgeeni retseptori geenide varieeruvus ei olnud seotud PCOS-iga. Lisaks näitasime, et menopausi algusaega mõjutavad geenivariandid on seotud munasarja funktsiooni ja viljatusravi tulemuslikkuse parameetritega, ja tulevikus võiks neid kombineerituna kliiniliste andmetega kaaluda võimalike biomarkeritena. Antud töö andis uut teavet naise viljakuse ja viljatuse geneetika kohta, kuid ühtlasi rõhutas edasiste uuringute vajalikkust.A wise man once said that the reproduction of mankind is a great marvel and mystery, and he was absolutely right, considering how many couples actually tackle with infertility. In Estonia, the majority of female infertility cases are due to tubal infertility (TFI) that is mostly caused by sexually transmitted infections, and polycystic ovary syndrome (PCOS), which is an endocrine disorder characterised by androgen excess and insulin resistance. In vitro fertilisation can help achieve pregnancy in these cases, but unfortunately the pregnancy rate per treatment cycle is only 30% and depends greatly on how the ovaries respond to the treatment. Over the years, great effort has been directed towards elucidating the molecular mechanisms behind the conditions causing infertility and it has been concluded that individual genetic variation is definitely one of the factors to blame. The studies of individual genetic variation form a good basis for finding biomarkers to predict natural reproductive function and perhaps even infertility treatment success. The general objective of the current thesis was to assess the associations between PCOS, TFI and selected candidate genes. In addition, several genetic variants that could be related to ovarian function and infertility treatment parameters were evaluated. Thus, DNA samples were collected from healthy women and infertile women and 47 genetic variants were studied in association with diagnoses of interest and different clinical parameters. In addition, to determine how many TFI cases are caused by a chlamydia infection, the prevalence of chlamydia-specific antibodies was measured in the blood sera of women with TFI. As a result, we found that ~50% of all TFI cases in Estonia might be caused by a previous chlamydia infection and identified genetic variants in the mannose binding lectin gene that modulate immune response and may be associated with susceptibility to TFI. No associations were found between selected variants in genes for insulin and androgen receptor and PCOS. However, we showed that genetic variants related to menopause timing are associated with ovarian function and infertility treatment parameters and could be considered as biomarker candidates if combined with clinical data. In conclusion, this study gave new knowledge about the genetics of female reproduction, but also highlighted the need for further research

Whole exome sequencing of benign pulmonary metastasizing leiomyoma reveals mutation in the BMP8B gene

Background: Benign metastasizing leiomyoma (BML) is an orphan neoplasm commonly characterized by pulmonary metastases consisting of smooth muscle cells. Patients with BML have usually a current or previous uterine leiomyoma, which is therefore suggested to be the most probable source of this tumour. The purpose of this case report was to determine the possible genetic grounds for pulmonary BML. Case presentation: We present a case report in an asymptomatic 44-year-old female patient, who has developed uterine leiomyoma with subsequent pulmonary BML. Whole exome sequencing (WES) was used to detect somatic mutations in BML lesion. Somatic single nucleotide mutations were identified by comparing the WES data between the pulmonary metastasis and blood sample of the same BML patient. One heterozygous somatic mutation was selected for validation by Sanger sequencing. Clonality of the pulmonary metastasis and uterine leiomyoma was assessed by X-chromosome inactivation assay. Conclusions: We describe a potentially deleterious somatic heterozygous mutation in bone morphogenetic protein 8B (BMP8B) gene (c.1139A > G, Tyr380Cys) that was identified in the pulmonary metastasis and was absent from blood and uterine leiomyoma, and may play a facilitating role in the metastasizing of BML. The clonality assay confirmed a skewed pattern of X-chromosome inactivation, suggesting monoclonal origin of the pulmonary metastases.Peer reviewe

2022. aasta inimgeneetikas

Eesti Arst 2023; 102(1):46–4

Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy

Abstract Study question: Can we identify genetic variants associated with ectopic pregnancy by undertaking the first genome-wide association study (GWAS) leveraging two large-scale biobank initiatives? Summary answer: We identified two novel genome-wide significant associations with ectopic pregnancy, highlighting MUC1 (mucin 1) as the most plausible affected gene. What is known already: Ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Despite being a common early pregnancy complication, the genetic predisposition to this condition remains understudied and no large scale genetic studies have been performed so far. Study design, size, duration: A GWAS meta-analysis including 7070 women with ectopic pregnancy and 248 810 controls from Estonian Biobank and the FinnGen study. Participants/materials, setting, methods: We identified ectopic pregnancy cases from national registers by ICD (International Classification of Disease) codes (ICD-10 O00), and all remaining women were considered controls. We carried out standard GWAS meta-analysis and additionally annotated GWAS signals, analysed co-localization with quantitative trait loci, estimated genetic correlations and identified associated phenotypes to characterize the genetic signals, as well as to analyse the genetic and phenotypic relationships with the condition. Main results and the role of change: We identified two genome-wide significant loci on chromosomes 1 (rs4971091, P = 5.32x10−9) and 10 (rs11598956, P = 2.41x10−8) potentially associated with ectopic pregnancy. Follow-up analyses propose MUC1, which codes for an epithelial glycoprotein with an important role in barrier function, as the most likely candidate gene for the association on chromosome 1. We also characterize the phenotypic and genetic correlations with other phenotypes, identifying a genetic correlation with smoking and diseases of the (genito)urinary and gastrointestinal system, and phenotypic correlations with various reproductive health diagnoses, reflecting the previously known epidemiological associations. Large scale data: The GWAS meta-analysis summary statistics are available from the GWAS Catalogue (GCST90272883). Limitations, reasons for caution: The main limitation is that the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes. Additionally, further larger meta-analysis or independent studies are needed to validate these findings. Wider implications of the findings: This study encourages the use of large-scale genetic datasets to unravel genetic factors linked to ectopic pregnancy, which is difficult to study in experimental settings. Increased sample size might bring additional genetic factors associating with ectopic pregnancy and inform its heritability. Altogether, our results provide more insight into the biology of ectopic pregnancy and, accordingly, the biological processes governing embryo implantation. Study funding(competing interest(s): N.P.G. was supported by MATER Marie Sklodowska-Curie which received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 813707. This study was funded by European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Computations were performed in the High-Performance Computing Center of University of Tartu. The authors declare no competing interests.Abstract Study question: Can we identify genetic variants associated with ectopic pregnancy by undertaking the first genome-wide association study (GWAS) leveraging two large-scale biobank initiatives? Summary answer: We identified two novel genome-wide significant associations with ectopic pregnancy, highlighting MUC1 (mucin 1) as the most plausible affected gene. What is known already: Ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Despite being a common early pregnancy complication, the genetic predisposition to this condition remains understudied and no large scale genetic studies have been performed so far. Study design, size, duration: A GWAS meta-analysis including 7070 women with ectopic pregnancy and 248 810 controls from Estonian Biobank and the FinnGen study. Participants/materials, setting, methods: We identified ectopic pregnancy cases from national registers by ICD (International Classification of Disease) codes (ICD-10 O00), and all remaining women were considered controls. We carried out standard GWAS meta-analysis and additionally annotated GWAS signals, analysed co-localization with quantitative trait loci, estimated genetic correlations and identified associated phenotypes to characterize the genetic signals, as well as to analyse the genetic and phenotypic relationships with the condition. Main results and the role of change: We identified two genome-wide significant loci on chromosomes 1 (rs4971091, P = 5.32x10−9) and 10 (rs11598956, P = 2.41x10−8) potentially associated with ectopic pregnancy. Follow-up analyses propose MUC1, which codes for an epithelial glycoprotein with an important role in barrier function, as the most likely candidate gene for the association on chromosome 1. We also characterize the phenotypic and genetic correlations with other phenotypes, identifying a genetic correlation with smoking and diseases of the (genito)urinary and gastrointestinal system, and phenotypic correlations with various reproductive health diagnoses, reflecting the previously known epidemiological associations. Large scale data: The GWAS meta-analysis summary statistics are available from the GWAS Catalogue (GCST90272883). Limitations, reasons for caution: The main limitation is that the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes. Additionally, further larger meta-analysis or independent studies are needed to validate these findings. Wider implications of the findings: This study encourages the use of large-scale genetic datasets to unravel genetic factors linked to ectopic pregnancy, which is difficult to study in experimental settings. Increased sample size might bring additional genetic factors associating with ectopic pregnancy and inform its heritability. Altogether, our results provide more insight into the biology of ectopic pregnancy and, accordingly, the biological processes governing embryo implantation. Study funding(competing interest(s): N.P.G. was supported by MATER Marie Sklodowska-Curie which received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 813707. This study was funded by European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Computations were performed in the High-Performance Computing Center of University of Tartu. The authors declare no competing interests

2024. aasta inimgeneetikas

Eesti Arst 2025; 104(4):241–24

Evidence From Men for Ovary-independent Effects of Genetic Risk Factors for Polycystic Ovary Syndrome

AbstractContext: Polycystic ovary syndrome (PCOS) is characterized by ovulatory dysfunction and hyperandrogenism and can be associated with cardiometabolic dysfunction, but it remains unclear which of these features are inciting causes and which are secondary consequences.Objective: To determine whether ovarian function is necessary for genetic risk factors for PCOS to produce nonreproductive phenotypes.Design, Setting, and Participants: Cohort of 176 360 men in the UK Biobank and replication cohort of 37 348 men in the Estonian Biobank.Main Outcome Measures: We calculated individual PCOS polygenic risk scores (PRS), tested for association of these PRS with PCOS-related phenotypes using linear and logistic regression and performed mediation analysis.Results: For every 1 SD increase in the PCOS PRS, men had increased odds of obesity (odds ratio [OR]: 1.09; 95% CI, 1.08-1.10; P = 1 × 10-49), type 2 diabetes mellitus (T2DM) (OR: 1.08; 95% CI, 1.05-1.10; P = 3 × 10-12), coronary artery disease (CAD) (OR: 1.03; 95% CI, 1.01-1.04; P = 0.0029), and marked androgenic alopecia (OR: 1.03; 95% CI, 1.02-1.05; P = 3 × 10-5). Body mass index (BMI), hemoglobin A1c, triglycerides, and free androgen index increased as the PRS increased, whereas high-density lipoprotein cholesterol and SHBG decreased (all P Conclusions: Genetic risk factors for PCOS have phenotypic consequences in men, indicating that they can act independently of ovarian function. Thus, PCOS in women may not always be a primary disorder of the ovaries.Abstract Context: Polycystic ovary syndrome (PCOS) is characterized by ovulatory dysfunction and hyperandrogenism and can be associated with cardiometabolic dysfunction, but it remains unclear which of these features are inciting causes and which are secondary consequences. Objective: To determine whether ovarian function is necessary for genetic risk factors for PCOS to produce nonreproductive phenotypes. Design, Setting, and Participants: Cohort of 176 360 men in the UK Biobank and replication cohort of 37 348 men in the Estonian Biobank. Main Outcome Measures: We calculated individual PCOS polygenic risk scores (PRS), tested for association of these PRS with PCOS-related phenotypes using linear and logistic regression and performed mediation analysis. Results: For every 1 SD increase in the PCOS PRS, men had increased odds of obesity (odds ratio [OR]: 1.09; 95% CI, 1.08-1.10; P = 1 × 10-49), type 2 diabetes mellitus (T2DM) (OR: 1.08; 95% CI, 1.05-1.10; P = 3 × 10-12), coronary artery disease (CAD) (OR: 1.03; 95% CI, 1.01-1.04; P = 0.0029), and marked androgenic alopecia (OR: 1.03; 95% CI, 1.02-1.05; P = 3 × 10-5). Body mass index (BMI), hemoglobin A1c, triglycerides, and free androgen index increased as the PRS increased, whereas high-density lipoprotein cholesterol and SHBG decreased (all P < .0001). The association between the PRS and CAD appeared to be completely mediated by BMI, whereas the associations with T2DM and marked androgenic alopecia appeared to be partially mediated by BMI. Conclusions: Genetic risk factors for PCOS have phenotypic consequences in men, indicating that they can act independently of ovarian function. Thus, PCOS in women may not always be a primary disorder of the ovaries

Endometrioos – anamneesist diagnoosini

Uuringu eesmärk. Töö eesmärgiks oli anda ülevaade aastatel 2005–2008 endometrioosile viitavate kaebustega naistearsti vastuvõtule pöördunud ning diagnostilise laparoskoopia/laparotoomia läbinud patsientide küsitluslehtede andmetest ning leida võimalikke endometrioosiga seotud kaebuseid ja riskitegureid. Metoodika. Retrospektiivne uuring, mille valimi moodustasid TÜ Kliinikumi naistekliinikus laparoskoopia/laparotoomia läbinud 170 naist, kellest 118-l (69,4%) diagnoositi endometrioos ja 52-l (30,6%) haigust ei tuvastatud. Patsiendid, kellel operatsiooni käigus endometrioosi ei tuvastatud, moodustasid edasistes analüüsides kontrollrühma. Tulemused ja järeldused. Uuringus osalenud endometrioosi ja kontrollrühma naiste üld- ja reproduktiivanamneesis olulisi erinevusi ei leitud, kuid endometrioosiga patsiendid kaebasid mõnevõrra sagedamini kogu menstruatsiooni kestel esinevaid alakõhuvalusid ning menstruatsiooniaegset valulikkust või veritsust defekatsioonil. Kontrollrühma naised olid sagedamini suitsetajad (32,7% vs 17,8%, p = 0,02) ning olid rohkem põdenud sugulisel teel levivaid haigusi (48,1% vs 25,4%, p = 0,01). Võrreldes endometrioosi mõõduka-raske vormiga esines minimaalse-kerge vormi korral sagedamini viljatust (vastavalt 34,7% ja 76,8%; p vs 27,5%; p = 0,02). Kokkuvõttes leidsime, et kogutud anamneesi ja kaebuste alusel on raske ennustada endometrioosi esinemist ja raskusastet. Diagnoos kinnitatakse vaid laparoskoopilise ja histoloogilise leiu põhjal. Endometrioosi kergemad vormid on aga seotud naise reproduktiivfunktsiooni häiretega – viljatuse ja spontaanabortidega. Eesti Arst 2011; 90(7):321–32

Leveraging Northern European population history : novel low-frequency variants for polycystic ovary syndrome

AbstractStudy question: Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe?Summary answer: We identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10).What is known already: PCOS is a common, complex disorder with unknown aetiology. While previous genome-wide association studies (GWAS) have mapped several loci associated with PCOS, the analysis of populations with unique population history and genetic makeup has the potential to uncover new low-frequency variants with larger effects.Study design, size, duration: A population-based case–control GWAS was carried out.Participants/materials, setting, methods: We identified PCOS cases from national registers by ICD codes (ICD-10 E28.2, ICD-9 256.4, or ICD-8 256.90), and all remaining women were considered controls. We then conducted a three-stage case–control GWAS: in the discovery phase, we had a total of 797 cases and 140 558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2812 cases and 89 230 controls. Finally, we performed a joint meta-analysis of 3609 cases and 229 788 controls from both cohorts. Additionally, we reran the association analyses including BMI as a covariate, with 2169 cases and 160 321 controls from both cohorts.Main results and the role of chance: Two out of the three novel genome-wide significant variants associating with PCOS, rs145598156 (P = 3.6×10−8, odds ratio (OR) = 3.01 [2.02–4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9×10−16, OR = 1.69 [1.49–1.91], MAF = 0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2 = 0.95) and a missense I157T (r2 = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 × 10−8, OR = 1.16 [1.10–1.23], MAF = 0.44). We also replicated four previous reported associations near the genes Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), DENN Domain Containing 1A (DENND1A), FSH Subunit Beta (FSHB) and Zinc Finger And BTB Domain Containing 16 (ZBTB16). When adding BMI as a covariate only one of the novel variants remained genome-wide significant in the meta-analysis (the EstBB lead signal in CHEK2 rs182075939, P = 1.9×10−16, OR = 1.74 [1.5–2.01]) possibly owing to reduced sample size.Large scale data: The age- and BMI-adjusted GWAS meta-analysis summary statistics are available for download from the GWAS Catalog with accession numbers GCST90044902 and GCST90044903.Limitations, reasons for caution: The main limitation was the low prevalence of PCOS in registers; however, the ones with the diagnosis most likely represent the most severe cases. Also, BMI data were not available for all (63% for FinnGen, 76% for EstBB), and the biobank setting limited the accessibility of PCOS phenotypes and laboratory values.Wider implications of the findings: This study encourages the use of isolated populations to perform genetic association studies for the identification of rare variants contributing to the genetic landscape of complex diseases such as PCOS.Study funding/competing interest(s): This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the MATER Marie Skłodowska-Curie grant agreement No. 813707 (N.P.-G., T.L., T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Läkaresällskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript. The authors declare no conflicts of interest.Abstract Study question: Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe? Summary answer: We identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10). What is known already: PCOS is a common, complex disorder with unknown aetiology. While previous genome-wide association studies (GWAS) have mapped several loci associated with PCOS, the analysis of populations with unique population history and genetic makeup has the potential to uncover new low-frequency variants with larger effects. Study design, size, duration: A population-based case–control GWAS was carried out. Participants/materials, setting, methods: We identified PCOS cases from national registers by ICD codes (ICD-10 E28.2, ICD-9 256.4, or ICD-8 256.90), and all remaining women were considered controls. We then conducted a three-stage case–control GWAS: in the discovery phase, we had a total of 797 cases and 140 558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2812 cases and 89 230 controls. Finally, we performed a joint meta-analysis of 3609 cases and 229 788 controls from both cohorts. Additionally, we reran the association analyses including BMI as a covariate, with 2169 cases and 160 321 controls from both cohorts. Main results and the role of chance: Two out of the three novel genome-wide significant variants associating with PCOS, rs145598156 (P = 3.6×10−8, odds ratio (OR) = 3.01 [2.02–4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9×10−16, OR = 1.69 [1.49–1.91], MAF = 0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2 = 0.95) and a missense I157T (r2 = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 × 10−8, OR = 1.16 [1.10–1.23], MAF = 0.44). We also replicated four previous reported associations near the genes Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), DENN Domain Containing 1A (DENND1A), FSH Subunit Beta (FSHB) and Zinc Finger And BTB Domain Containing 16 (ZBTB16). When adding BMI as a covariate only one of the novel variants remained genome-wide significant in the meta-analysis (the EstBB lead signal in CHEK2 rs182075939, P = 1.9×10−16, OR = 1.74 [1.5–2.01]) possibly owing to reduced sample size. Large scale data: The age- and BMI-adjusted GWAS meta-analysis summary statistics are available for download from the GWAS Catalog with accession numbers GCST90044902 and GCST90044903. Limitations, reasons for caution: The main limitation was the low prevalence of PCOS in registers; however, the ones with the diagnosis most likely represent the most severe cases. Also, BMI data were not available for all (63% for FinnGen, 76% for EstBB), and the biobank setting limited the accessibility of PCOS phenotypes and laboratory values. Wider implications of the findings: This study encourages the use of isolated populations to perform genetic association studies for the identification of rare variants contributing to the genetic landscape of complex diseases such as PCOS. Study funding/competing interest(s): This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the MATER Marie Skłodowska-Curie grant agreement No. 813707 (N.P.-G., T.L., T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Läkaresällskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript. The authors declare no conflicts of interest

Uniting biobank resources reveals novel genetic pathways modulating susceptibility for atopic dermatitis

Publisher Copyright: © 2021 The AuthorsBackground: Atopic dermatitis (AD) is a common chronic inflammatory skin disease with high heritability. Previous genome-wide association studies have identified several loci predisposing to AD. These findings explain approximately 30% of the variance in AD susceptibility, suggesting that further work is required to fully understand the genetic underpinnings. Objective: We sought to gain additional understanding of the genetic contribution to AD risk by using biobank resources. Methods: We completed a genome-wide meta-analysis of AD in 796,661 individuals (Ncases = 22,474) from the FinnGen study, the Estonian Biobank, and the UK Biobank. We further performed downstream in silico analyses to characterize the risk variants at the novel loci. Results: We report 30 loci associating with AD (P < 5 × 10−8), 5 of which are novel. In 2 of the novel loci, we identified missense mutations with deleterious predictions in desmocollin 1 and serpin family B member 7, genes encoding proteins crucial to epidermal strength and integrity. Conclusions: These findings elucidate novel genetic pathways involved in AD pathophysiology. The likely involvement of desmocollin 1 and serpin family B member 7 in AD pathogenesis may offer opportunities for the development of novel treatment strategies for AD in the future.Peer reviewe