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Abstract Background Male androgenetic alopecia (AGA) has been implicated as a putative risk factor in severe COVID‐19 based on high incidences of advanced AGA in male hospitalized COVID‐19 patients. Research further suggests that androgen signalling, which plays a central role in AGA aetiology, promotes SARS‐CoV‐2 infection and is associated with severe COVID‐19 symptoms in men. Objectives We aimed to systematically investigate a potential association between AGA and COVID‐19 both on an epidemiological and a genetic level in a large single‐population cohort. Methods We performed regression, genetic correlation and polygenic risk score (PRS) analyses using data from the UK Biobank and published GWAS data on AGA and COVID‐19. Results Our analyses did not reveal any significant epidemiological or genome‐wide genetic association between AGA and severe COVID‐19. Pathway‐based PRS analyses however revealed a significant association in specific pathways, namely vitamin metabolism, natural killer cell‐mediated cytotoxicity, WNT signalling and aryl hydrocarbon receptor signalling. Limitations We restricted our analyses to the white British population and used self‐reported AGA status. Sample size may be a limitation in our regression and PRS analyses. Conclusions Our data yield no evidence for an epidemiological association between AGA and COVID‐19 but suggest that a shared genetic basis for both traits exists in specific pathways.

Abstract Introduction There is conflicting evidence whether high‐density lipoprotein cholesterol (HDL‐C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL‐C. We aimed to assess AD risk by genetically predicted HDL‐C. Methods Ten single nucleotide polymorphisms within the CETP locus predicting HDL‐C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR‐Egger. Results Based on 10 single nucleotide polymorphisms distinctly predicting HDL‐C in the CETP locus, we found that HDL‐C was not associated with risk of AD (P > .7). Discussion Our study does not support the role of HDL‐C on risk of AD through HDL‐C altered by CETP. This study does not rule out other mechanisms by which HDL‐C affects risk of AD.

Duplications of the Xq28,distal locus have been described in male and female patients with schizophrenia (SCZ) or intellectual disability. The Xq28,distal locus spans eight protein-coding genes (F8, CMC4, MTCP1, BRCC3, VBP1, FUNDC2, CLIC2, and RAB39B) and is flanked by recurrent genomic breakpoints. Thus, the issue of which gene/s at this locus is/are relevant in terms of SCZ pathogenesis remains unclear. The aim of this study was to investigate the contribution of rare and potentially functionally relevant sequence variants within the Xq28,distal locus to SCZ risk using the single-molecule molecular inversion probes (smMIP) method. Targeted sequencing was performed in a cohort of 1935 patients with SCZ and 1905 controls of European ancestry. The consecutive statistical analysis addressed two main areas. On the level of the individual variants, allele counts in the patient and control cohort were systematically compared with a Fisher's exact test: (i) for the entire present study cohort; (ii) for patients and controls separated by sex; and (iii) in combination with data published by the Schizophrenia Exome Meta-Analysis (SCHEMA) consortium. On the gene-wise level, a burden analysis was performed using the X-chromosomal model of the Optimal Unified Sequence Kernel Association Test (SKAT-O), with adjustment for possible sex-specific effects. Targeted sequencing identified a total of 13 rare and potentially functional variants in four patients and 11 controls. However, neither at the level of individual rare and potentially functional variants nor at the level of the eight protein-coding genes at the Xq28,distal locus was a statistically significant enrichment in patients compared to controls observed. Although inconclusive, the present findings represent a step toward improved understanding of the contribution of X-chromosomal risk factors in neuropsychiatric disorder development, which is an underrepresented aspect of genetic studies in this field., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Background: Given the great interest in identifying reliable predictors of the response to antidepressant drugs, the present study investigated whether polygenic scores (PGS) for Major Depressive Disorder (MDD) and antidepressant treatment response (ADR) were related to the complex trait of antidepressant response in the Early Medication Change (EMC) cohort., Methods: In this secondary analysis of the EMC trial (N = 889), 481 MDD patients were included and compared to controls from a population-based cohort. Patients were treated over eight weeks within a pre-defined treatment-algorithm. We investigated patients' genetic variation associated with MDD and ADR, using PGS and examined the association of PGS with treatment outcomes (early improvement, response, remission). Additionally, the influence of two cytochrome P450 drug-metabolizing enzymes (CYP2C19, CYP2D6) was determined., Results: PGS for MDD was significantly associated with disorder status (NkR 2  = 2.48 %, p < 1*10 -12 ), with higher genetic burden in EMC patients compared to controls. The PGS for ADR did not explain remission status. The PGS for MDD and ADR were also not associated with treatment outcomes. In addition, there were no effects of common CYP450 gene variants on ADR., Limitations: The study was limited by variability in the outcome parameters due to differences in treatment and insufficient sample size in the used ADR genome-wide association study (GWAS)., Conclusions: The present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes., Competing Interests: Declaration of competing interest A Tadic is designated as inventor of the European patent number 12171541.1–2404 ‘Method for predicting response or non-response to a mono-aminergic antidepressant’. He has received during the last five years consultancy fees from Janssen and ROVI. K Lieb is designated as inventor of the European patent number 12171541.1–2404 ‘Method for predicting response or non-response to a mono-aminergic antidepressant’. S Heilmann-Heimbach and P Hoffmann are employees at Life&Brain GmbH, Bonn. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Resilience is the capacity to adapt to stressful life events. As such, this trait is associated with physical and mental functions and conditions. Here, we aimed to identify the genetic factors contributing to shape resilience. We performed variant- and gene-based meta-analyses of genome-wide association studies from six German cohorts (N = 15822) using the 11-item version of the Resilience Scale (RS-11) as outcome measure. Variant- and gene-level results were combined to explore the biological context using network analysis. In addition, we conducted tests of correlation between RS-11 and the polygenic scores (PGSs) for 12 personality and mental health traits in one of these cohorts (PROCAM-2, N = 3879). The variant-based analysis found no signals associated with resilience at the genome-wide level (p < 5 × 10 -8 ), but suggested five genomic loci (p < 1 × 10 -5 ). The gene-based analysis identified three genes (ROBO1, CIB3 and LYPD4) associated with resilience at genome-wide level (p < 2.48 × 10 -6 ) and 32 potential candidates (p < 1 × 10 -4 ). Network analysis revealed enrichment of biological pathways related to neuronal proliferation and differentiation, synaptic organization, immune responses and vascular homeostasis. We also found significant correlations (FDR < 0.05) between RS-11 and the PGSs for neuroticism and general happiness. Overall, our observations suggest low heritability of resilience. Large, international efforts will be required to uncover the genetic factors that contribute to shape trait resilience. Nevertheless, as the largest investigation of the genetics of resilience in general population to date, our study already offers valuable insights into the biology potentially underlying resilience and resilience's relationship with other personality traits and mental health., (© 2024. The Author(s).)

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies., Competing Interests: Per Hoffmann receives Salary from the Life & Brain GmbH, Bonn, Germany. James L. Kennedy is a member of the Scientific Advisory Board for Myriad Neuroscience Inc. Ian B. Hickie was an inaugural Commissioner on Australia’s National Mental Health Commission (2012-18). He is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017-20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. Andrew M. Mcintosh has received research support from Eli Lilly, Janssen, and The Sackler Trust. AMM has also received speaker fees from Illumina and Janssen. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He is paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. Joel Gelernter is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018 and issued on January 26, 2021 as U.S. Patent No. 10,900,082; and is paid for editorial work for the journal “Complex Psychiatry.” Iiris Hovatta received speaker’s honoraria from Lundbeck. Ole A. Andreassen received speaker’s honorarium from Lundbeck and Sunovion, consultant for Cortechs.ai and Precision Health AS. Katharina Domschke has been a member of the Steering Committee Neurosciences, Janssen, Inc. until 2022 and is currently a member of the Board of the German National Society of Psychiatry (DGPPN) and the Neurotorium Editorial Board of the Lundbeck Foundation. Jordan W. Smoller is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received an honorarium for an internal seminar Tempus Labs. He is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. Eduard Maron has received research support and has also received speaker fees from Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Indorsia, Neuraxpharm, Servier and Janssen Cilag. Henrik Larsson has served as a speaker for Evolan Pharma, Medici and Shire/Takeda and has received research grants from Shire/Takeda; all outside the submitted work. Gerome Breen is an advisory board member for Compass Pathways. Jürgen Deckert is a member of the board of the German Society of Biological Psychiatry and is on the scientific advisory boards of non-profit organizations and foundations. Volker Arolt worked as an advisor for Sanofi-Adventis Germany. Zach Fuller and Xin Wang are employees of 23andMe and hold stock or stock options in 23andMe. All other authors have no competing interests to declare.

Background: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited., Objective: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology., Methods: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE., Results: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort., Conclusions: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: In bipolar disorder (BD), immunological factors play a role in the pathogenesis and treatment of the illness. Studies showed the potential link between Abelson Helper Integration Site 1 (AHI1) protein, behavioural changes and innate immunity regulation. An immunomodulatory effect was suggested for lithium, a mood stabilizer used in BD treatment., Objectives: We hypothesized that AHI1 may be an important mediator of lithium treatment response. Our study aimed to investigate whether the AHI1 haplotypes and expression associates with lithium treatment response in BD patients. We also examined whether AHI1 expression and lithium treatment correlate with innate inflammatory response genes., Results: We genotyped seven AHI1 single nucleotide polymorphisms in 97 euthymic BD patients and found that TG haplotype (rs7739635, rs9494332) was significantly associated with lithium response. We also showed significantly increased AHI1 expression in the blood of lithium responders compared to non-responders and BD patients compared to healthy controls (HC). We analyzed the expression of genes involved in the innate immune response and inflammatory response regulation (TLR4, CASP4, CASP5, NLRP3, IL1A, IL1B, IL6, IL10, IL18) in 21 lithium-treated BD patients, 20 BD patients treated with other mood stabilizer and 19 HC. We found significantly altered expression between BD patients and HC, but not between BD patients treated with different mood stabilizers., Conclusions: Our study suggests the involvement of AHI1 in the lithium mode of action. Moreover, mood-stabilizing treatment associated with the innate immunity-related gene expression in BD patients and only the lithium-treated BD patients showed significantly elevated expression of anti-inflammatory IL10, suggesting lithium's immunomodulatory potential., (© 2023. The Author(s).)

Introduction: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities., Methods: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population., Results: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10 -23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose., Discussion: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations., Highlights: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Short anagen hair (SAH) is a rare paediatric hair disorder characterized by a short anagen phase, an inability to grow long scalp hair and a negative psychological impact. The genetic basis of SAH is currently unknown., Objectives: To perform molecular genetic investigations in 48 individuals with a clinical phenotype suggestive of SAH to identify, if any, the genetic basis of this condition., Methods: Exome sequencing was performed in 27 patients diagnosed with SAH or with a complaint of short, nongrowing hair. The cohort was screened for variants with a minor allele frequency (MAF) < 5% in the general population and a Combined Annotation Dependent Depletion (CADD) score > 15, to identify genes whose variants were enriched in this cohort. Sanger sequencing was used for variant validation and screening of 21 additional individuals with the same clinical diagnosis and their relatives. Genetic association testing of SAH-related variants for male pattern hair loss (MPHL) was performed using UK Biobank data., Results: Analyses revealed that 20 individuals (42%) carried mono- or biallelic pathogenic variants in WNT10A. Rare WNT10A variants are associated with a phenotypic spectrum ranging from no clinical signs to severe ectodermal dysplasia. A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-coloured hair and regression of the frontoparietal hairline. Notably, the most frequent variant in the cohort [c.682T>A;p.(Phe228Ile)] was in linkage disequilibrium with four common WNT10A variants, all of which have a known association with MPHL. Using UK Biobank data, our analyses showed that c.682T>A;p.(Phe228Ile) and one other variant identified in the SAH cohort are also associated with MPHL, and partially explain the known associations between WNT10A and MPHL., Conclusions: Our results suggest that WNT10A is associated with SAH and that SAH has a genetic overlap with the common phenotype MPHL. The presumed shared biologic effect of WNT10A variants in SAH and MPHL is a shortening of the anagen phase. Other factors, such as modifier genes and sex, may also play a role in the clinical manifestation of hair phenotypes associated with the WNT10A locus., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights., Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses., Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine., Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Male-pattern hair loss (MPHL) is common and highly heritable. While genome-wide association studies (GWAS) have generated insights into the contribution of common variants to MPHL etiology, the relevance of rare variants remains unclear. To determine the contribution of rare variants to MPHL etiology, we perform gene-based and single-variant analyses in exome-sequencing data from 72,469 male UK Biobank participants. While our population-level risk prediction suggests that rare variants make only a minor contribution to general MPHL risk, our rare variant collapsing tests identified a total of five significant gene associations. These findings provide additional evidence for previously implicated genes (EDA2R, WNT10A) and highlight novel risk genes at and beyond GWAS loci (HEPH, CEPT1, EIF3F). Furthermore, MPHL-associated genes are enriched for genes considered causal for monogenic trichoses. Together, our findings broaden the MPHL-associated allelic spectrum and provide insights into MPHL pathobiology and a shared basis with monogenic hair loss disorders., (© 2023. Springer Nature Limited.)

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Introduction: We constructed a polygenic risk score (PRS) for β-amyloid (PRSAβ42) to proxy AD pathology and investigated its association with incident Alzheimer's disease (AD)/amnestic mild cognitive impairment (aMCI) and the influence of cognitive reserve (CR), proxied by educational years, on the relationship between PRSAβ42 and AD/aMCI risk., Methods: A total of 618 cognitive-normal participants were followed-up for 2.92 years. The association of PRSAβ42 and CR with AD/aMCI incidence was examined with COX models. Then we examined the additive interaction between PRSAβ42 and CR and the CR effect across participants with different PRSAβ42 levels., Results: Higher PRSAβ42 and CR were associated with a 33.9% higher risk and 8.3% less risk for AD/aMCI, respectively. An additive interaction between PRSAβ42 and CR was observed. High CR was associated with 62.6% less risk of AD/aMCI incidence only in the high-PRSAβ42 group., Discussion: A super-additive effect of PRSAβ42 and CR on AD/aMCI risk was observed. CR influence was evident in participants with high PRSAβ42., (© 2023 the Alzheimer's Association.)

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia., Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention., Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022., Exposures: Genetically determined modifiable risk factors., Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors., Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50])., Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Male-pattern hair loss (MPHL) is a highly heritable and prevalent condition that is characterized by progressive hair loss from the frontotemporal and vertex scalp. This androgen-dependent hair loss may commence during puberty, and up to 80 % of European men experience some degree of MPHL during their lifetime. Current treatment options for MPHL have limited efficacy, and improved understanding of the underlying biological causes is required to facilitate novel therapeutic approaches. To date, molecular genetic studies have identified 389 associated genomic regions, have implicated numerous genes in these regions, and suggested pathways that are likely to contribute to key pathophysiological mechanisms in MPHL. This review provides an overview of the current status of MPHL genetic research. We discuss the most significant achievements, current challenges, and anticipated developments in the field, as well as their potential to advance our understanding of hair (loss) biology, and to improve hair loss prediction and treatment., (© 2023 bei den Autorinnen und Autoren, publiziert von De Gruyter.)

Genetic prediction of male pattern baldness (MPB) is important in science and society. Previous genetic MPB prediction models were limited by sparse marker coverage, small sample size, and/or data dependency in the different analytical steps. Here, we present novel models for genetic prediction of MPB based on a large set of markers and large independent subsample sets drawn among 187,435 European subjects. We selected 117 SNP predictors within 85 distinct loci from a list of 270 previously MPB-associated SNPs in 55,573 males of the UK Biobank Study (UKBB). Based on these 117 SNPs with and without age as additional predictor, we trained, by use of different methods, prediction models in a non-overlapping subset of 104,694 UKBB males and tested them in a non-overlapping subset of 26,177 UKBB males. Estimates of prediction accuracy were similar between methods with AUC ranges of 0.725-0.728 for severe, 0.631-0.635 for moderate, 0.598-0.602 for slight, and 0.708-0.711 for no hair loss with age, and slightly lower without, while prediction of any versus no hair loss gave 0.690-0.711 with age and slightly lower without. External validation in an early-onset enriched MPB dataset from the Bonn Study (N = 991) showed improved prediction accuracy without considering age such as AUC of 0.830 for no vs. any hair loss. Because of the large number of markers and the large independent datasets used for the different analytical steps, the newly presented genetic prediction models are the most reliable ones currently available for MPB or any other human appearance trait., (© 2022. The Author(s).)

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorders (SZ) exhibit considerable phenotypic and genetic overlap. However, the contribution of genetic factors to their shared psychopathological symptom dimensions remains unclear. The present exploratory study investigated genetic contributions to the symptom dimensions "Depression", "Negative syndrome", "Positive formal thought disorder", "Paranoid-hallucinatory syndrome", and "Increased appetite" in a transdiagnostic subset of the German FOR2107 cohort (n = 1042 patients with MDD, BD, or SZ). As replication cohort, a subset of the German/Austrian PsyCourse study (n = 816 patients with MDD, BD, or SZ) was employed. First, the relationship between symptom dimensions and common variants associated with MDD, BD, and SZ was investigated via polygenic risk score (PRS) association analyses, with disorder-specific PRS as predictors and symptom dimensions as outcomes. In the FOR2107 study sample, PRS for BD and SZ were positively associated with "Positive formal thought disorder", the PRS for SZ was positively associated with "Paranoid-hallucinatory syndrome", and the PRS for BD was negatively associated with "Depression". The effects of PRS for SZ were replicated in PsyCourse. No significant associations were observed for the MDD PRS. Second, genome-wide association studies (GWAS) were performed for the five symptom dimensions. No genome-wide significant associations and no replicable suggestive associations (p < 1e-6 in the GWAS) were identified. In summary, our results suggest that, similar to diagnostic categories, transdiagnostic psychiatric symptom dimensions are attributable to polygenic contributions with small effect sizes. Further studies in larger thoroughly phenotyped psychiatric cohorts are required to elucidate the genetic factors that shape psychopathological symptom dimensions., Competing Interests: Declaration of competing interest TK received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm. ECS received funding through the Munich Clinician Scientist Program (MCSP). All other authors report no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: numerous studies point towards a critical role of Interleukin 6 (IL-6) pathway in frailty pathogenesis yet the causal relationship between the two remains elusive., Methods: we selected genetic variants near the IL-6 receptor locus (IL-6R) associated with reduced C-reactive protein (CRP) levels, a downstream effector of IL-6 pathway, and we used them as genetic proxies of IL-6 signalling downregulation. We then performed a two-sample Mendelian randomisation (MR) to investigate the association with frailty status, as defined by the Frailty Index (FI) in 11,171 individuals from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD) study. MR analysis was repeated after excluding depression or cognition-related FI items as well as following age or sex stratification. Association with frailty was also examined using an alternative instrument, weighted on s-IL-6R levels. Replication was attempted in UK Biobank dataset., Results: genetic predisposition to IL-6 signalling downregulation, weighted on CRP levels, was associated with lower risk of frailty, inserted either as categorical (odds ratio [95% confidence interval] = 0.15 [-3.39, -0.40], P = 0.013) or continuous variable (beta [se] = -0.09 [0.003], P = 0.0009). Sensitivity analyses revealed similar estimates across different MR methods with no evidence for horizontal pleiotropy or heterogeneity. Results remained robust after exclusion of depression or cognition-related FI items and following sex or age stratification. Genetically increased s-IL-6R levels were negatively correlated with frailty and this finding remained significant in a meta-analysis of UK Biobank and HELIAD cohorts., Conclusion: our results support a potential causal effect of IL-6 signalling on frailty and further suggest that downregulation of IL-6 levels may reduce frailty risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit ( p = 4.22 × 10 -20 ) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

Anorectal malformations (ARM) represent a spectrum of rare malformations originating from a perturbated development of the embryonic hindgut. Approximately 60% occur as a part of a defined genetic syndrome or within the spectrum of additional congenital anomalies. Rare copy number variations (CNVs) have been associated with both syndromic and non-syndromic forms. The present study represents the largest study to date to explore the contribution of CNVs to the expression of ARMs. SNP-array-based molecular karyotyping was applied in 450 individuals with ARM and 4392 healthy controls. CNVs were identified from raw intensity data using PennCNV. Overlapping CNVs between cases and controls were discarded. Remaining CNVs were filtered using a stringent filter algorithm of nine filter steps. Prioritized CNVs were confirmed using qPCR. Filtering prioritized and qPCR confirmed four microscopic chromosomal anomalies and nine submicroscopic CNVs comprising seven microdeletions (del2p13.2, del4p16.2, del7q31.33, del9p24.1, del16q12.1, del18q32, del22q11.21) and two microduplications (dup2p13.2, dup17q12) in 14 individuals (12 singletons and one affected sib-pair). Within these CNVs, based on their embryonic expression data and function, we suggest FOXK2, LPP, and SALL3 as putative candidate genes. Overall, our CNV analysis identified putative microscopic and submicroscopic chromosomal rearrangements in 3% of cases. Functional characterization and re-sequencing of suggested candidate genes is warranted., (© 2022. The Author(s).)

Personality traits influence risk for suicidal behavior. We examined phenotype- and genotype-level associations between the Big Five personality traits and suicidal ideation and attempt in major depressive, bipolar and schizoaffective disorder, and schizophrenia patients (N = 3012) using fixed- and random-effects inverse variance-weighted meta-analyses. Suicidal ideations were more likely to be reported by patients with higher neuroticism and lower extraversion phenotypic scores, but showed no significant association with polygenic load for these personality traits. Our findings provide new insights into the association between personality and suicidal behavior across mental illnesses and suggest that the genetic component of personality traits is unlikely to have strong causal effects on suicidal behavior., (© 2022. The Author(s).)

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The diagnostic criteria for schizophrenia (SCZ) and bipolar disorder (BD) are based on clinical assessments of symptoms. In this pilot study, we applied high-throughput antibody-based protein profiling to serum samples of healthy controls and individuals with SCZ and BD with the aim of identifying differentially expressed proteins in these disorders. Moreover, we explored the influence of polygenic burden for SCZ and BD on the serum levels of these proteins. Serum samples from 113 individuals with SCZ and 125 with BD from the PsyCourse Study and from 44 healthy controls were analyzed by using a set of 155 antibodies in an antibody-based assay targeting a selected panel of 95 proteins. For the cases, genotyping and imputation were conducted for DNA samples and SCZ and BD polygenic risk scores (PRS) were calculated. Univariate linear and logistic models were used for association analyses. The comparison between SCZ and BD revealed two serum proteins that were significantly elevated in BD after multiple testing adjustment: "complement C9" and "Interleukin 1 Receptor Accessory Protein". Moreover, the first principal component of variance in the proteomics dataset differed significantly between SCZ and BD. After multiple testing correction, SCZ-PRS, BD-PRS, and SCZ-vs-BD-PRS were not significantly associated with the levels of the individual proteins or the values of the proteome principal components indicating no detectable genetic effects. Overall, our findings contribute to the evidence suggesting that the analysis of circulating proteins could lead to the identification of distinctive biomarkers for SCZ and BD. Our investigation warrants replication in large-scale studies to confirm these findings., (© 2022. The Author(s).)

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT 3 receptor family. 5-HT 3 Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT 3 R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D., (© 2022. The Author(s).)

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume., (© 2022. The Author(s).)

Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes ( SERPING1 , F12 , PLG , ANGPT1 , and KNG1 ) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p -value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p .adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mathey, Maj, Scheer, Fazaal, Wedi, Wieczorek, Amann, Löffler, Koch, Schöffl, Dickel, Ganjuur, Hornung, Forkel, Greve, Wurpts, Hallberg, Bygum, Von Buchwald, Karawajczyk, Steffens, Stingl, Hoffmann, Heilmann-Heimbach, Mangold, Ludwig, Rasmussen, Wadelius, Sachs, Nöthen and Forstner.)

Context: Approximately 70% of infertile men are diagnosed with idiopathic (abnormal semen parameters) or unexplained (normozoospermia) infertility, with the common feature of lacking etiologic factors. Follicle-stimulating hormone (FSH) is essential for initiation and maintenance of spermatogenesis. Certain single-nucleotide variations (SNVs; formerly single-nucleotide polymorphisms [SNPs]) (ie, FSHB c.-211G > T, FSHR c.2039A > G) are associated with FSH, testicular volume, and spermatogenesis. It is unknown to what extent other variants are associated with FSH levels and therewith resemble causative factors for infertility., Objective: We aimed to identify further genetic determinants modulating FSH levels in a cohort of men presenting with idiopathic or unexplained infertility., Methods: We retrospectively (2010-2018) selected 1900 men with idiopathic/unexplained infertility. In the discovery study (n = 760), a genome-wide association study (GWAS) was performed (Infinium PsychArrays) in association with FSH values (Illumina GenomeStudio, v2.0). Minor allele frequencies (MAFs) were analyzed for the discovery and an independent normozoospermic cohort. In the validation study (n = 1140), TaqMan SNV polymerase chain reaction was conducted for rs11031005 and rs10835638 in association with andrological parameters., Results: Imputation revealed 9 SNVs in high linkage disequilibrium, with genome-wide significance (P < 4.28e-07) at the FSHB locus 11p.14.1 being associated with FSH. The 9 SNVs accounted for up to a 4.65% variance in FSH level. In the oligozoospermic subgroup, this was increased up to 6.95% and the MAF was enhanced compared to an independent cohort of normozoospermic men. By validation, a significant association for rs11031005/rs10835638 with FSH (P = 4.71e-06/5.55e-07) and FSH/luteinizing hormone ratio (P = 2.08e-12/6.4e-12) was evident., Conclusions: This GWAS delineates the polymorphic FSHB genomic region as the main determinant of FSH levels in men with unexplained or idiopathic infertility. Given the essential role of FSH, molecular detection of one of the identified SNVs that causes lowered FSH and therewith decreases spermatogenesis could resolve the idiopathic/unexplained origin by this etiologic factor., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly., Objective: To determine whether rare missense variants on APOE are associated with AD risk., Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021., Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression., Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers., Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

Androgenetic alopecia (AGA) is a prevalent hair loss condition in males that develops due to the influence of androgens and genetic predisposition. With the aim of elucidating genes involved in AGA pathogenesis, we modelled AGA with three-dimensional culture of keratinocyte-surrounded dermal papilla (DP) cells. We co-cultured immortalised balding and non-balding human DP cells (DPCs) derived from male AGA patients with epidermal keratinocyte (NHEK) using multi-interfacial polyelectrolyte complexation technique. We observed up-regulated mitochondria-related gene expression in balding compared with non-balding DP aggregates which indicated altered mitochondria metabolism. Further observation of significantly reduced electron transport chain complex activity (complexes I, IV and V), ATP levels and ability to uptake metabolites for ATP generation demonstrated compromised mitochondria function in balding DPC. Balding DP was also found to be under significantly higher oxidative stress than non-balding DP. Our experiments suggest that application of antioxidants lowers oxidative stress levels and improves metabolite uptake in balding DPC. We postulate that the observed up-regulation of mitochondria-related genes in balding DP aggregates resulted from an over-compensatory effort to rescue decreased mitochondrial function in balding DP through the attempted production of new functional mitochondria. In all, our three-dimensional co-culturing revealed mitochondrial dysfunction in balding DPC, suggesting a metabolic component in the aetiology of AGA., (© 2022 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR < 0.05), but not the ventral striatum of AUD cases. In the VS, DE genes at FDR < 0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune- and inflammation-related processes in AUD., (© 2022. The Author(s).)

Induction of neoangiogenesis is a hallmark feature during disease progression of hepatocellular carcinoma (HCC). Antiangiogenetic compounds represent a mainstay of therapeutic approaches; however, development of chemoresistance is observed in the majority of patients. Recent findings suggest that tumor-initiating cells (TICs) may play a key role in acquisition of resistance, but the exact relevance for HCC in this process remains to be defined. Primary and established hepatoma cell lines were exposed to long-term sorafenib treatment to model acquisition of resistance. Treatment effects on TICs were estimated by sphere-forming capacity in vitro, tumorigenicity in vivo, and flow cytometry. Adaptive molecular changes were assessed by whole transcriptome analyses. Compensatory mechanisms of resistance were identified and directly evaluated. Sustained antiproliferative effect following sorafenib treatment was observed in three of six HCC cell lines and was followed by rapid regrowth, thereby mimicking responses observed in patients. Resistant cells showed induction in sphere forming in vitro and tumor-initiating capacity in vivo as well as increased number of side population and epithelial cell adhesion molecule-positive cells. Conversely, sensitive cell lines showed consistent reduction of TIC properties. Gene sets associated with resistance and poor prognosis, including Hippo/yes-associated protein (YAP), were identified. Western blot and immunohistochemistry confirmed increased levels of YAP. Combined treatment of sorafenib and specific YAP inhibitor consistently revealed synergistic antioncogenic effects in resistant cell lines. Conclusion: Resistance to antiangiogenic therapy might be driven by transient expansion of TICs and activation of compensatory pro-oncogenic signaling pathways, including YAP. Specific targeting of TICs might be an effective therapeutic strategy to overcome resistance in HCC., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood., Methods: We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors., Results: We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy., Conclusions: This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences).

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., (© 2022. The Author(s).)

Nonsyndromic cleft lip with or without palate (nsCL/P) ranks among the most common human birth defects and has a multifactorial etiology. Human neural crest cells (hNCC) make a substantial contribution to the formation of facial bone and cartilage and are a key cell type in terms of nsCL/P etiology. Based on increasing evidence for the role of noncoding regulatory mechanisms in nsCL/P, we investigated the role of hNCC-expressed microRNAs (miRNA) in cleft development. First, we conducted a systematic analysis of miRNAs expressed in human-induced pluripotent stem cell-derived hNCC using Affymetrix microarrays on cell lines established from 4 unaffected donors. These analyses identified 152 candidate miRNAs. Based on the hypothesis that candidate miRNA loci harbor genetic variation associated with nsCL/P risk, the genomic locations of these candidates were cross-referenced with data from a previous genome-wide association study of nsCL/P. Associated variants were reanalyzed in independent nsCL/P study populations. Jointly, the results suggest that miR-149 is implicated in nsCL/P etiology. Second, functional follow-up included in vitro overexpression and inhibition of miR-149 in hNCC and subsequent analyses at the molecular and phenotypic level. Using 3'RNA-Seq, we identified 604 differentially expressed (DE) genes in hNCC overexpressing miR-149 compared with untreated cells. These included TLR4 and JUNB , which are established targets of miR-149, and NOG , BMP4 , and PAX6 , which are reported nsCL/P candidate genes. Pathway analyses revealed that DE genes were enriched in pathways including regulation of cartilage development and NCC differentiation. At the cellular level, distinct hNCC migration patterns were observed in response to miR-149 overexpression. Our data suggest that miR-149 is involved in the etiology of nsCL/P via its role in hNCC migration.

Alcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls (n = 58) using a brain-region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted correlation network analysis (WGCNA), gene-set, and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < 0.05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < 0.05) were found in the CN (n = 6), VS (n = 18), and ACC (n = 1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD., (© 2021. The Author(s).)

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10 -8 ; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10 -10 ; OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10 -16 ; OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes., Competing Interests: The co-author C.M.B. declares the following interests: Shire (grant recipient, Scientific Advisory Board member), Idorsia (consultant), Lundbeckfonden (grant recipient), Pearson (author, royalty recipient), and Equip Health Inc. (Clinical Advisory Board). All other co-authors declare no competing interests., (© 2022 The Authors.)

Background: Frailty is a complex geriatric syndrome arising from a combination of genetic and environmental factors and is associated with adverse health outcomes and mortality. A recent study reported an association between variants of the 9p21-23 locus, associated with a number of age-related disorders, including Alzheimer's disease (AD), and frailty. Frailty has been associated with increased risk of developing AD and it has been proposed that frailty burden may modify AD clinical presentation. In view of the overlapping genetic architecture between the two disorders, it is noteworthy to conduct studies to uncover risk variants that contribute to both AD and frailty. The purpose of this study is to test the reproducibility of the association of 9p21-23 locus with frailty in a population that is ethnically different from previous work and in the context of multidimensional definitions of frailty that will allow us to examine the potential impact to domains pertaining to AD pathology., Methods: We operationalized frailty according two definitions and the corresponding instruments, the Frailty Index (FI) and the Tilburg Frailty Indicator (TFI) and we determined genotypes of eight alleles previously identified as risk increasing for frailty in 1172 community-dwelling older participants (57% females) from the HELIAD study with a mean age of 74 years old. We cross-sectionally investigated the association between risk alleles and frailty, as well as with specific components of each definition using linear regression analyses adjusted for age, sex and years of education., Results: Compared to non-carriers, carriers of rs7038172 C risk allele, were associated with a higher FI Score (β=0.089, p=0.002). Similarly, we found a positive association between the presence of at least one rs7038172 C variant and TFI score (β=0.053, p=0.04). Moreover, the rs7038172 variant was associated, irrespectively of dementia status, with the memory and psychological domain of FI and TFI, respectively., Conclusion: Our study confirms the association of the rs7038172 C allele with the frailty syndrome in a Greek population and in the context of multidimensional definitions of frailty. Furthermore, we report novel associations between this allele and the memory domain of FI and the psychological domain of TFI, that includes memory problems on its components. Given that frailty burden has been shown to modify the AD clinical presentation, it is likely that rs7038172 C allele may accelerate the transition of AD or frailty to dementia Overall, our study corroborates the role of the 9p21-23 region in frailty development and draw potential links with AD pathology., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Objectives: Bipolar disorder (BD) has a highly heterogeneous clinical course that is characterized by relapses and increased health care utilization in a significant fraction of patients. A thorough understanding of factors influencing illness course is essential for predicting disorder severity and developing targeted therapies., Methods: We performed polygenic score analyses in four cohorts (N = 954) to test whether the genetic risk for BD, schizophrenia, or major depression is associated with a severe course of BD. We analyzed BD patients with a minimum illness duration of five years. The severity of the disease course was assessed by using the number of hospitalizations in a mental health facility and a composite measure of longitudinal illness severity (OPCRIT item 90)., Results: Our analyses showed that higher polygenic scores for BD (β = 0.11, SE = 0.03, p = 1.17 × 10 -3 ) and schizophrenia (β = 0.09, SE = 0.03, p = 4.24 × 10 -3 ), but not for major depression, were associated with more hospitalizations. None of the investigated polygenic scores was associated with the composite measure of longitudinal illness severity (OPCRIT item 90)., Limitations: We could not account for non-genetic influences on disease course. Our clinical sample contained more severe cases., Conclusions: This study demonstrates that the genetic risk burden for psychiatric illness is associated with increased health care utilization, a proxy for disease severity, in BD patients. The findings are in line with previous observations made for patients diagnosed with schizophrenia or major depression. Therefore, in the future psychiatric disorder polygenic scores might become helpful for stratifying patients with high risk of a chronic manifestation and predicting disease course., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Several studies have investigated the association of the Parkinson's disease (PD) polygenic risk score (PRS) with several aspects of well-established PD. We sought to evaluate the association of PRS with the prodromal stage of PD. We calculated PRS in a longitudinal sample ( n = 1120) of community dwelling individuals ≥ 65 years from the HELIAD (The Hellenic Longitudinal Investigation of Aging and Diet) study in order to evaluate the association of this score with the probability of prodromal PD or any of the established risk and prodromal markers in MDS research criteria, using regression multi-adjusted models. Increases in PRS estimated from GWAS summary statistics' ninety top SNPS with p < 5 × 10 -8 was associated with increased odds of having probable/possible prodromal PD (i.e., ≥ 30% probability, OR = 1.033, 95%CI: 1.009-1.057 p = 0.006). From the prodromal PD risk markers, significant association was found between PRS and global cognitive deficit exclusively ( p = 0.003). To our knowledge, our study is the first population based study investigating the association between PRS scores and prodromal markers of Parkinson's disease. Our results suggest a strong relationship between the accumulation of many common genetic variants, as measured by PRS, and cognitive deficits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Maraki, Hatzimanolis, Mourtzi, Stefanis, Yannakoulia, Kosmidis, Dardiotis, Hadjigeorgiou, Sakka, Ramirez, Grenier-Boley, Lambert, Heilmann-Heimbach, Stamelou, Scarmeas and Xiromerisiou.)

Background: Male androgenetic alopecia (AGA) has been implicated as a putative risk factor in severe COVID-19 based on high incidences of advanced AGA in male hospitalized COVID-19 patients. Research further suggests that androgen signalling, which plays a central role in AGA aetiology, promotes SARS-CoV-2 infection and is associated with severe COVID-19 symptoms in men., Objectives: We aimed to systematically investigate a potential association between AGA and COVID-19 both on an epidemiological and a genetic level in a large single-population cohort., Methods: We performed regression, genetic correlation and polygenic risk score (PRS) analyses using data from the UK Biobank and published GWAS data on AGA and COVID-19., Results: Our analyses did not reveal any significant epidemiological or genome-wide genetic association between AGA and severe COVID-19. Pathway-based PRS analyses however revealed a significant association in specific pathways, namely vitamin metabolism, natural killer cell-mediated cytotoxicity, WNT signalling and aryl hydrocarbon receptor signalling., Limitations: We restricted our analyses to the white British population and used self-reported AGA status. Sample size may be a limitation in our regression and PRS analyses., Conclusions: Our data yield no evidence for an epidemiological association between AGA and COVID-19 but suggest that a shared genetic basis for both traits exists in specific pathways., Competing Interests: The authors declare no conflict of interests., (© 2021 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are frequent and serious complications after surgery. We aim to investigate the association between genetic variants in cholinergic candidate genes according to the Kyoto encyclopedia of genes and genomes - pathway: cholinergic neurotransmission with the development of POD or POCD in elderly patients., Methods: This analysis is part of the European BioCog project ( www.biocog.eu ), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini-Mental-State-Examination score ≤ 23 points were excluded. POD was assessed up to seven days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. POCD was assessed three months after surgery with a neuropsychological test battery. Genotyping was performed on the Illumina Infinium Global Screening Array. Associations with POD and POCD were analyzed using logistic regression analysis, adjusted for age, comorbidities and duration of anesthesia (for POCD analysis additionally for education). Odds ratios (OR) refer to minor allele counts (0, 1, 2)., Results: 745 patients could be included in the POD analysis, and 452 in the POCD analysis. The rate of POD within this group was 20.8% (155 patients), and the rate of POCD was 10.2% (46 patients). In a candidate gene approach three genetic variants of the cholinergic genes CHRM2 and CHRM4 were associated with POD (OR [95% confidence interval], rs8191992: 0.61[0.46; 0.80]; rs8191992: 1.60[1.22; 2.09]; rs2067482: 1.64[1.10; 2.44]). No associations were found for POCD., Conclusions: We found an association between genetic variants of CHRM2 and CHRM4 and POD. Further studies are needed to investigate whether disturbances in acetylcholine release and synaptic plasticity are involved in the development of POD., Trial Registration: ClinicalTrials.gov: NCT02265263., (© 2021. The Author(s).)