medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Июль 18, 2024
Autism Spectrum Disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes ASD pathogenesis, such as
Язык: Английский
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Март 15, 2024
Summary Large biobanks, such as the UK Biobank (UKB), enable massive phenome by genome-wide association studies that elucidate genetic etiology of complex traits. However, individuals from diverse ancestry groups are often excluded analyses due to concerns about population structure introducing false positive associations. Here, we generate mixed model associations and meta-analyses across groups, inclusive a larger fraction UKB than previous efforts, produce freely-available summary statistics for 7,266 We build quality control analysis framework informed architecture. Overall, identify 14,676 significant loci (p < 5 x 10 -8 ) in meta-analysis were not found EUR group alone, including novel example between CAMK2D triglycerides. also highlight ancestry-enriched variation, known pleiotropic missense variant G6PD associated with several biomarker release these results publicly alongside FAQs describe caveats interpretation results, enhancing available resources risk variants populations.
Язык: Английский
Процитировано
66
JAMA Neurology, Год журнала: 2024, Номер unknown
Опубликована: Сен. 9, 2024
Importance The X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion genes expressed brain, making particularly appealing as potential source unexplored genetic variation AD. Objectives To perform first large-scale chromosome–wide association study (XWAS) Design, Setting, Participants This was meta-analysis studies case-control, family-based, population-based, longitudinal AD-related cohorts from US Alzheimer’s Disease Genetics Consortium, Sequencing Project, UK Biobank, Finnish health registry, Million Veterans Program. Risk AD evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 March 2024. Genetic data available high-density single-nucleotide variant microarrays whole-genome sequencing summary statistics for multitissue expression protein quantitative trait loci published included, enabling follow-up colocalization A total 1 629 863 eligible participants selected referred volunteer samples, 477 596 whom excluded analysis exclusion criteria. number who declined to participate original not available. Main Outcome Measures AD, reported odds ratios (ORs) with 95% CIs. Associations considered at ( P &lt; × 10 −5 ) genome-wide 5 −8 significance. Primary analyses are nonstratified, while secondary evaluate sex-stratified effects. Results Analyses included 152 284 non-Hispanic White, European ancestry (664 403 [57.7%] female 487 881 [42.3%] male), including 138 558 individuals Six independent passed significance, 4 showing support links signal nearby brain nonbrain tissues. One these conservative its lead centered on an intron SLC9A7 (OR, 1.03; CI, 1.02-1.04) prioritizing both CHST7 genes. Of 6 loci, displayed evidence escape inactivation regard risk. Conclusion Relevance XWAS identified novel locus. regulates pH homeostasis Golgi secretory compartments is anticipated have downstream effects amyloid β accumulation. Overall, this advances our knowledge genetics may provide biological drug targets. results further initial insights into elucidating role sex-based differences
Язык: Английский
Процитировано
11
Genes, Год журнала: 2024, Номер 15(5), С. 617 - 617
Опубликована: Май 12, 2024
Mitochondrial DNA (mtDNA) exhibits distinct characteristics distinguishing it from the nuclear genome, necessitating specific analytical methods in genetic studies. This comprehensive review explores complex role of mtDNA a variety studies, including genome-wide, epigenome-wide, and phenome-wide association with focus on its implications for human traits diseases. Here, we discuss structure gene-encoding properties mtDNA, along influence environmental factors epigenetic modifications function variability. Particularly significant are challenges posed by mtDNA's high mutation rate, heteroplasmy, copy number variations, their impact disease susceptibility population analyses. The also highlights recent advances methodological approaches that enhance our understanding associations, advocating refined research techniques accommodate complexities. By providing overview intricacies this paper underscores need an integrated approach to studies considers unique mitochondrial genetics. Our findings aim inform future encourage development innovative methodologies better interpret broad health disease.
Язык: Английский
Процитировано
10
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Янв. 2, 2025
Abstract The biological mechanisms underlying women’s increased Alzheimer’s disease (AD) prevalence remain undefined. Previous case/control studies have identified sex-biased molecular pathways, but sex-specific relationships between gene expression and AD endophenotypes, particularly sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated associations post-mortem β-amyloid tau as well antemortem longitudinal cognition. Of 23,118 significant associations, 10% were in one not the other (sex-specific). Most females (73%) associated with tangles cognition (90%). Four X-linked genes, MCF2 , HDAC8 FTX SLC10A3 demonstrated differences their endophenotypes (i.e., x interaction). Our results also uncovered including a female-specific role of neuroinflammation neuronal development, reinforcing potential for sex-aware analyses to enhance precision medicine approaches AD.
Язык: Английский
Процитировано
1
Science Advances, Год журнала: 2025, Номер 11(10)
Опубликована: Март 5, 2025
Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive (Xi) active (Xa), in contrast males with only Xa. Thus, reactivation of silent Xi genes may contribute differences. We use allele-specific, single-nucleus RNA sequencing show that aging remodels transcription the Xa across hippocampal cell types. Aging preferentially changed gene expression on X's relative autosomes. Select underwent activation, new escape cells including dentate gyrus, critical learning memory. Expression escapee Plp1, a myelin component, was increased hippocampus female mice parahippocampus women. AAV-mediated Plp1 elevation gyrus male improved cognition. Understanding how confer advantage could lead novel targets counter brain disease both sexes.
Язык: Английский
Процитировано
1
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Апрель 23, 2024
The X chromosome has remained enigmatic in Alzheimer's disease (AD), yet it makes up 5% of the genome and carries a high proportion genes expressed brain, making particularly appealing as potential source unexplored genetic variation AD.
Язык: Английский
Процитировано
4
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Май 10, 2024
Abstract Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral cortex: 377, hippocampus: 394), we identified 831 unique genes that exhibit across brain regions, enriched immune-related pathways. We observed X-chromosome dosage reduction hippocampus of individuals schizophrenia. Our interaction model revealed 148 junctions dysregulated sex-specific manner Sex-specific analysis dozens differentially expressed genes, notably Finally, our sex-interacting expression quantitative trait loci 704 nine associated risk. These findings emphasize importance sex-informed traits, inform personalized therapeutic strategies schizophrenia, highlight need increased female samples analyses.
Язык: Английский
Процитировано
4
Cell Genomics, Год журнала: 2024, Номер 4(8), С. 100625 - 100625
Опубликована: Июль 30, 2024
Several X-linked genes escape from X chromosome inactivation (XCI), while differences in across cell types and tissues are still poorly characterized. Here, we developed scLinaX for directly quantifying relative gene expression the inactivated with droplet-based single-cell RNA sequencing (scRNA-seq) data. The differentially expressed analyses large-scale blood scRNA-seq datasets consistently identified stronger lymphocytes than myeloid cells. An extension of to a 10x multiome dataset (scLinaX-multi) suggested cells at chromatin-accessibility level. analysis human multiple-organ also relatively strong degree XCI lymphoid lymphocytes. Finally, effect size comparisons genome-wide association studies between sexes underlying impact on genotype-phenotype association. Overall, quantified catalog heterogeneity tissues.
Язык: Английский
Процитировано
4
The Transmitter, Год журнала: 2025, Номер unknown
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
0
Science Advances, Год журнала: 2025, Номер 11(4)
Опубликована: Янв. 24, 2025
Genes on the X chromosome are extensively expressed in human brain. However, little is known for chromosome’s impact brain anatomy, microstructure, and functional networks. We examined 1045 complex imaging traits from 38,529 participants UK Biobank. unveiled potential autosome–X interactions while proposing an atlas outlining dosage compensation traits. Through extensive association studies, we identified 72 genome-wide significant trait-locus pairs (including 29 new associations) that share genetic architectures with brain-related disorders, notably schizophrenia. Furthermore, found unique sex-specific associations assessed variations effects between sexes. Our research offers critical insights into role brain, underscoring its contribution to differences observed structure functionality
Язык: Английский
Процитировано
0