A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents

AbstractVisceral adiposity has been associated with altered microstructural properties of white matter in adolescents. Previous evidence suggests that circulating phospholipid PC(16:0/2:0) may mediate this association. To investigate the underlying biology, we performed a genome-wide association study (GWAS) of the shared variance of visceral fat, PC(16:0/2:0), and white matter microstructure in 872 adolescents from the Saguenay Youth Study. We further studied the metabolomic profile of the GWAS-lead variant in 931 adolescents. Visceral fat and white matter microstructure were assessed with magnetic resonance imaging. Circulating metabolites were quantified with serum lipidomics and metabolomics. We identified a genome-wide significant association near DHCR24 (Seladin-1) encoding a cholesterol-synthesizing enzyme (rs588709, p = 3.6 × 10−8); rs588709 was also associated nominally with each of the three traits (white matter microstructure: p = 2.1 × 10−6, PC(16:0/2:0): p = 0.005, visceral fat: p = 0.010). We found that the metabolic profile associated with rs588709 resembled that of a TM6SF2 variant impacting very low-density lipoprotein (VLDL) secretion and was only partially similar to that of a HMGCR variant. This suggests that the effect of rs588709 on VLDL lipids may arise due to altered phospholipid rather than cholesterol metabolism. The rs588709 was also nominally associated with circulating concentrations of omega-3 fatty acids in interaction with visceral fat and PC(16:0/2:0), and these fatty acid measures showed robust associations with white matter microstructure. Overall, the present study provides evidence that the DHCR24 locus may link peripheral metabolism to brain microstructure, an association with implications for cognitive impairment.Abstract Visceral adiposity has been associated with altered microstructural properties of white matter in adolescents. Previous evidence suggests that circulating phospholipid PC(16:0/2:0) may mediate this association. To investigate the underlying biology, we performed a genome-wide association study (GWAS) of the shared variance of visceral fat, PC(16:0/2:0), and white matter microstructure in 872 adolescents from the Saguenay Youth Study. We further studied the metabolomic profile of the GWAS-lead variant in 931 adolescents. Visceral fat and white matter microstructure were assessed with magnetic resonance imaging. Circulating metabolites were quantified with serum lipidomics and metabolomics. We identified a genome-wide significant association near DHCR24 (Seladin-1) encoding a cholesterol-synthesizing enzyme (rs588709, p = 3.6 × 10−8); rs588709 was also associated nominally with each of the three traits (white matter microstructure: p = 2.1 × 10−6, PC(16:0/2:0): p = 0.005, visceral fat: p = 0.010). We found that the metabolic profile associated with rs588709 resembled that of a TM6SF2 variant impacting very low-density lipoprotein (VLDL) secretion and was only partially similar to that of a HMGCR variant. This suggests that the effect of rs588709 on VLDL lipids may arise due to altered phospholipid rather than cholesterol metabolism. The rs588709 was also nominally associated with circulating concentrations of omega-3 fatty acids in interaction with visceral fat and PC(16:0/2:0), and these fatty acid measures showed robust associations with white matter microstructure. Overall, the present study provides evidence that the DHCR24 locus may link peripheral metabolism to brain microstructure, an association with implications for cognitive impairment

TUFT1, a novel candidate gene for metatarsophalangeal osteoarthritis, plays a role in chondrogenesis on a calcium-related pathway

Osteoarthritis (OA) is the most common degenerative joint disorder and genetic factors have been shown to have a significant role in its etiology. The first metatarsophalangeal joint (MTP I) is highly susceptible to development of OA due to repetitive mechanical stress during walking. We used whole exome sequencing to study genetic defect(s) predisposing to familial early-onset bilateral MTP I OA inherited in an autosomal dominant manner. A non-synonymous single nucleotide variant rs41310883 (c.524C>T, p.Thr175Met) in TUFT1 gene was found to co-segregate perfectly with MTP I OA. The role of TUFT1 and the relevance of the identified variant in pathogenesis of MTP I OA were further assessed using functional in vitro analyses. The variant reduced TUFT1 mRNA and tuftelin protein expression in HEK293 cells. ATDC5 cells overexpressing wild type (wt) or mutant TUFT1 were cultured in calcifying conditions and chondrogenic differentiation was found to be inhibited in both cell populations, as indicated by decreased marker gene expression when compared with the empty vector control cells. Also, the formation of cartilage nodules was diminished in both TUFT1 overexpressing ATDC5 cell populations. At the end of the culturing period the calcium content of the extracellular matrix was significantly increased in cells overexpressing mutant TUFT1 compared to cells overexpressing wt TUFT1 and control cells, while the proteoglycan content was reduced. These data imply that overexpression of TUFT1 in ATDC5 inhibits chondrogenic differentiation, and the identified variant may contribute to the pathogenesis of OA by increasing calcification and reducing amount of proteoglycans in the articular cartilage extracellular matrix thus making cartilage susceptible for degeneration and osteophyte formation

Role of oxysterol 4β-hydroxycholesterol and liver X receptor alleles in pre-eclampsia

Abstract Background Liver X receptors (LXRs) are expressed in placenta and may be associated with pre-eclampsia (PE). Oxysterols act as agonists for LXRs. We recently proposed a new blood pressure-regulating circuit with oxysterol 4β-hydroxycholesterol (4βHC) acting as a hypotensive factor via LXRs. Materials and methods This study investigated the association between maternal plasma 4βHC, blood pressure (BP) indices, placental expression of LXR target genes, and patient characteristics using data from the Finnish Genetics of Pre-Eclampsia Consortium (FINNPEC) cohort. Plasma samples of 144 women with PE and 38 healthy pregnant controls as well as 44 PE and 40 control placental samples were available. In addition, genetic data from the FinnGen project was utilized to explore the associations of LXR alleles with PE and pregnancy hypertension. Results There were no significant associations between 4βHC and BP or maternal and perinatal characteristics in FINNPEC cohort. However, plasma 4βHC was inversely correlated with the maternal body mass index. There were no associations with the genetic variants of LXRs with PE in FinnGen. LXR target genes APOD, SCARB1, TGM2, and LPCAT3 were expressed differently between PE and normal pregnancies in placental samples of FINNPEC. Conclusions Our results demonstrate that plasma 4βHC and genetic LXR variants do not play a major role in PE and BP regulation during pregnancy. However, key LXR target genes involved in lipid metabolism were expressed differently in normal and PE pregnancies. Further research is needed to understand the complexities of oxysterols, LXRs, and their potential contributions to placental function and pregnancy outcomes.Abstract Background Liver X receptors (LXRs) are expressed in placenta and may be associated with pre-eclampsia (PE). Oxysterols act as agonists for LXRs. We recently proposed a new blood pressure-regulating circuit with oxysterol 4β-hydroxycholesterol (4βHC) acting as a hypotensive factor via LXRs. Materials and methods This study investigated the association between maternal plasma 4βHC, blood pressure (BP) indices, placental expression of LXR target genes, and patient characteristics using data from the Finnish Genetics of Pre-Eclampsia Consortium (FINNPEC) cohort. Plasma samples of 144 women with PE and 38 healthy pregnant controls as well as 44 PE and 40 control placental samples were available. In addition, genetic data from the FinnGen project was utilized to explore the associations of LXR alleles with PE and pregnancy hypertension. Results There were no significant associations between 4βHC and BP or maternal and perinatal characteristics in FINNPEC cohort. However, plasma 4βHC was inversely correlated with the maternal body mass index. There were no associations with the genetic variants of LXRs with PE in FinnGen. LXR target genes APOD, SCARB1, TGM2, and LPCAT3 were expressed differently between PE and normal pregnancies in placental samples of FINNPEC. Conclusions Our results demonstrate that plasma 4βHC and genetic LXR variants do not play a major role in PE and BP regulation during pregnancy. However, key LXR target genes involved in lipid metabolism were expressed differently in normal and PE pregnancies. Further research is needed to understand the complexities of oxysterols, LXRs, and their potential contributions to placental function and pregnancy outcomes

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

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

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 = 3.6x10(-8), odds ratio (OR) = 3.01 [2.02-4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9x10(-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 (r(2) = 0.95) and a missense I157T (r(2) = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 x 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 = 1.9x10(-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 Sklodowska-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 Lakaresallskapet (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.Peer reviewe

Genetic study of psoriasis highlights its close link with socio-economic status and affective symptoms

Abstract Psoriasis is an inflammatory skin disease with an estimated heritability of around 70%. Previous GWASs have detected several risk loci for psoriasis. To further improve the understanding of the genetic risk factors impacting the disease, we conducted a discovery GWAS in FinnGen and a subsequent replication and meta-analysis with data from the Estonian Biobank and the UK Biobank; the study sample included 925,649 individuals (22,659 cases and 902,990 controls), the largest sample for psoriasis yet. In addition, we conducted downstream analyses to find out more about psoriasis’ cross-trait genetic correlations and causal relationships. We report 6 risk loci, which, to our knowledge, are previously unreported, most of which harbor genes related to NF-κB signaling pathway and overall immunity. Genetic correlations highlight the relationship between psoriasis and smoking, higher body weight, and lower education level. In addition, we report causal relationships between psoriasis and mood symptoms as well as 2-directioned causal relationship between psoriasis and lower education level. Our results provide further knowledge on psoriasis risk factors, which may be useful in the development of future treatment strategies.Abstract Psoriasis is an inflammatory skin disease with an estimated heritability of around 70%. Previous GWASs have detected several risk loci for psoriasis. To further improve the understanding of the genetic risk factors impacting the disease, we conducted a discovery GWAS in FinnGen and a subsequent replication and meta-analysis with data from the Estonian Biobank and the UK Biobank; the study sample included 925,649 individuals (22,659 cases and 902,990 controls), the largest sample for psoriasis yet. In addition, we conducted downstream analyses to find out more about psoriasis’ cross-trait genetic correlations and causal relationships. We report 6 risk loci, which, to our knowledge, are previously unreported, most of which harbor genes related to NF-κB signaling pathway and overall immunity. Genetic correlations highlight the relationship between psoriasis and smoking, higher body weight, and lower education level. In addition, we report causal relationships between psoriasis and mood symptoms as well as 2-directioned causal relationship between psoriasis and lower education level. Our results provide further knowledge on psoriasis risk factors, which may be useful in the development of future treatment strategies

Visceral adiposity is associated with metabolic profiles predictive of type 2 diabetes and myocardial infarction

Background: Visceral fat (VF) increases risk for cardiometabolic disease (CMD), the leading cause of morbidity and mortality. Variations in the circulating metabolome predict the risk for CMD but whether or not this is related to VF is unknown. Further, CMD is now also present in adolescents, and the relationships between VF, circulating metabolome, and CMD may vary between adolescents and adults. Methods: With an aim to add understanding to the metabolic variations in visceral obesity, we tested associations between VF, measured directly with magnetic resonance imaging, and 228 fasting serum metabolomic measures, quantified with nuclear magnetic resonance spectroscopy, in 507 adults (36-65 years) and 938 adolescents (12-18 years). We further utilized data from published studies to estimate similarities between VF and CMD-associated metabolic profiles. Results: Here we show that VF, independently of body mass index (BMI) or subcutaneous fat, is associated with triglyceride-rich lipoproteins, fatty acids, and inflammation in both adults and adolescents, whereas the associations with amino acids, glucose, and intermediary metabolites are significant in adults only. BMI-adjusted metabolomic profile of VF resembles those predicting type 2 diabetes in adults (R 2 = 0.88) and adolescents (R 2 = 0.70), and myocardial infarction in adults (R 2 = 0.59) and adolescents (R 2 = 0.40); this is not the case for ischemic stroke (adults: R 2 = 0.05, adolescents: R 2 = 0.08). Conclusions: Visceral adiposity is associated with metabolomic profiles predictive of type 2 diabetes and myocardial infarction even in normal-weight individuals and already in adolescence. Targeting factors contributing to the emergence and maintenance of these profiles might ameliorate their cumulative effects on cardiometabolic health

Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns

Background Inflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood. Objective To assess genetic determinants of 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Finns. Methods Genome-wide associations of the inflammatory phenotypes were studied in Northern Finland Birth Cohort 1966 (N=5284). A subsequent meta-analysis was completed for 10 phenotypes available in a previous genome-wide association study, adding up to 13 577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels. Results We identified seven novel and six previously reported genetic associations (p Conclusion The present results extend the knowledge about genetic factors contributing to the inflammatory load. Our findings suggest that two distinct mechanisms contribute to the soluble adhesion molecule levels in the ABO locus and that elevated soluble adhesion molecule levels per se may not increase risk for cardiovascular disease.Peer reviewe

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

Background: 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 -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.Keywords: Atopic dermatitis; DSC1; FinnGen; SERPINB7; genome-wide association.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.</p