Trans-ancestry Genome-Wide Analyses in UK Biobank Yield Novel Risk Loci for Major Depression

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Most genome-wide association studies (GWASs) of depression focus on broad, heterogeneous outcomes, limiting the discovery genomic risk loci specific to major depressive disorder (MDD). Previous UK Biobank (UKB) had limited ability pinpoint MDD-associated due a smaller sample with strictly defined MDD outcomes and further exclusion many participants based ancestry or relatedness, significantly underutilizing this resource's potential for elucidating genetic architecture MDD. Here, we present novel insights into by fully utilizing existing UKB data through (1) trans-ancestry GWAS pipeline using two complementary approaches controlling population structure relatedness (2) an increased symptom-level across mental health assessments. We identified strict among 211,535 participants, representing 38% increase in eligible from prior only one assessment. Ancestrally inclusive analyses yielded 61 phenotypes, compared 47 restricted genetically similar European ancestry. Fourteen these loci, including five novel, were associated whereas locus has been previously reported UKB. predicted gene expression levels showed little overlap broad depression, indicating higher specificity. Notably, polygenic scores results diagnoses groups All Us Research Program, highlighting shared populations. While analyses, which included non-European number ancestry-specific was limited, underscoring need larger, globally representative Importantly, beyond results, our will facilitate other traits disorders, helping improve statistical power, representation, generalizability studies.

Язык: Английский

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Identification of 16 novel Alzheimer's disease loci using multi‐ancestry meta‐analyses

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(2)

Опубликована: Фев. 1, 2025

Abstract INTRODUCTION Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD‐associated genetic determinants have been identified, few studies analyzed individuals non‐European ancestry. METHODS We conducted a multi‐ancestry genome‐wide association study (GWAS) clinically diagnosed AD and AD‐by‐proxy using whole genome sequencing data from National Institute on Aging Genetics Disease Data Storage Site (NIAGADS), Mental Health, UK Biobank (UKB), All Us (AoU) consisting 49,149 cases (12,074 37,075 AD‐by‐proxy) 383,225 controls. Nearly half NIAGADS AoU participants were RESULTS For AD, we identified 14 new loci—five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) nine rare (VWA5B1, RNU6‐755P/LMX1A, MOB1A, MORC1‐AS1, LINC00989, PDE4D, RNU2‐49P/CDO1, NEO1, SLC35G3/AC022916.1). Meta‐analysis UKB yielded two loci (RPL23/LASP1 CEBPA/AC008738.6), also nominally significant in NIAGADS. DISCUSSION In summary, provide evidence for 16 novel advocate more sequencing–based GWAS diverse cohorts. Highlights used whole‐genome large found findings based data. performed multiancestry meta‐analysis incorporated results underrepresented groups.

Язык: Английский

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Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease

Cell Reports, Год журнала: 2025, Номер unknown, С. 115355 - 115355

Опубликована: Март 1, 2025

Highlights•ITSN1 haploinsufficiency confers a ∼10-fold increased risk of Parkinson's disease (PD)•Effect size surpasses other well-established loci, including GBA1 and LRRK2•In vivo in vitro studies suggest an interaction between ITSN1 α-synuclein•Findings implicate synaptic vesicle trafficking dysfunction PD pathogenesisSummaryDespite its significant heritability, the genetic basis (PD) remains incompletely understood. Here, analyzing whole-genome sequence data from 3,809 cases 247,101 controls UK Biobank, we discover that protein-truncating variants confer substantially (p = 6.1 × 10−7; odds ratio [95% confidence interval] 10.5 [5.2, 21.3]). We replicate this association three independent datasets totaling 8,407 413,432 (combined p 4.5 10−12). Notably, has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, find loss ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity motor deficits, assays further physical α-synuclein. These results firmly establish as gene effect exceeding previously established vesicular pathogenesis, potentially open new avenues for therapeutic development.Graphical abstract

Язык: Английский

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LILRB3 genetic variation is associated with kidney transplant failure in African American recipients

Nature Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 10, 2025

Язык: Английский

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GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 12, 2025

Abstract Sarcoidosis is a complex inflammatory disease with strong genetic component. Here, we perform genome-wide association study in 9755 sarcoidosis cases to identify risk loci and map associated genes. We then use transcriptome-wide studies enrichment analyses explore pathways involved Mendelian randomization examine associations modifiable factors circulating biomarkers. 28 genomic sarcoidosis, the C1orf141-IL23R locus showing largest effect size. observe gene expression patterns related spleen, whole blood, lung, highlight 75 tissue-specific genes through studies. Furthermore, analysis establish key roles for T cell activation, leukocyte adhesion, cytokine production sarcoidosis. Additionally, find between genetically predicted body mass index, interleukin-23 receptor, eight proteins.

Язык: Английский

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