Functional insight into East Asian–specific genetic risk loci for Alzheimer's disease

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

Опубликована: Фев. 1, 2025

Abstract INTRODUCTION The functional study of genetic risk factors for Alzheimer's disease (AD) provides insights into the underlying mechanisms and identification potential therapeutic targets. Investigating AD‐associated loci identified in East Asian populations using single‐nucleus RNA‐sequencing data may identify novel contributors. METHODS Cell type–specific expression quantitative trait (eQTL) peak‐to‐gene links were used to genes associated with 26 from seven genome‐wide association studies (GWAS) AD Asians. RESULTS KCNJ6 MAPK1IP1L as significant eQTLs loci. peaks related four genes, CLIC4 being connected across different cell types. Genes European GWAS interacted within networks enriched pathology pathways astrocytes. DISCUSSION Our findings suggest providing insight architecture Highlights Integrated analysis was performed. (eQTLs) assay transposase‐accessible chromatin genes. An variant linked through an oligodendrocyte progenitor cell–specific eQTL. maps open chromatin, six Astrocyte differentially expressed by are

Язык: Английский

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The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment

Journal of Neuroscience, Год журнала: 2023, Номер 43(10), С. 1830 - 1844

Опубликована: Янв. 30, 2023

The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimer's disease (AD). It parent β-amyloid (Aβ) peptide, main constituent plaques found in an AD brain. pathways from APP Aβ are intensively studied, yet normal functions itself have generated less interest. We report here that glutamate stimulation neuronal activity leads a rapid increase App gene expression. In mouse human neurons, elevated changes structure axon initial segment (AIS) where action potentials initiated. AIS shortened length shifts away cell body. GCaMP8f Ca 2+ reporter confirms predicted decrease activity. NMDA antagonists or knockdown block effects. actions on cell-autonomous; exogenous Aβ, either fibrillar oligomeric, has no effect. culture, Swe (a familial mutation) induces larger than wild type APP. Ankyrin G βIV-spectrin, scaffolding proteins AIS, both physically associate with APP, more so brains. Finally, humans sporadic R1.40 model, females males, neurons levels invade AIS. vivo as vitro , this increased associated significant shortening findings outline new role for encourage reconsideration its relationship AD. SIGNIFICANCE STATEMENT While long been (AD), full-length Type I membrane largely unexplored. modest amounts excess alter properties segment. peptide derived without Consistent observed which would be expected potential firing, we show expression depresses models AD, associates segment, suggesting dementia.

Язык: Английский

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The Collaborative Study on the Genetics of Alcoholism: Overview

Genes Brain & Behavior, Год журнала: 2023, Номер 22(5)

Опубликована: Сен. 22, 2023

Abstract Alcohol use disorders (AUD) are commonly occurring, heritable and polygenic with etiological origins in the brain environment. To outline causes consequences of alcohol‐related milestones, including AUD, their related psychiatric comorbidities, Collaborative Study on Genetics Alcoholism (COGA) was launched 1989 a gene‐brain‐behavior framework. COGA is family based, diverse (~25% self‐identified African American, ~52% female) sample, data 17,878 individuals, ages 7–97 years, 2246 families which proportion densely affected for AUD. All participants responded to questionnaires (e.g., personality) Semi‐Structured Assessment (SSAGA) gathers information diagnoses, conditions behaviors parental monitoring). In addition, 9871 individuals have function from electroencephalogram (EEG) recordings while 12,009 been genotyped genome‐wide association study (GWAS) arrays. A series functional genomics studies examine specific cellular molecular mechanisms underlying This overview provides framework development as scientific resource past three decades, individual reviews providing in‐depth descriptions discoveries behavioral clinical, function, genetic data. The value also resides its sharing policies, efforts communicate findings broader community via project website potential nurture early career investigators generate independent research that has broadened impact into

Язык: Английский

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The collaborative study on the genetics of alcoholism: Genetics

Genes Brain & Behavior, Год журнала: 2023, Номер 22(5)

Опубликована: Июнь 30, 2023

Abstract This review describes the genetic approaches and results from family‐based Collaborative Study on Genetics of Alcoholism (COGA). COGA was designed during linkage era to identify genes affecting risk for alcohol use disorder (AUD) related problems, among first AUD‐focused studies subsequently adopt a genome‐wide association (GWAS) approach. COGA's structure, multimodal assessment with gold‐standard clinical neurophysiological data, availability prospective longitudinal phenotyping continues provide insights into etiology AUD disorders. These include investigations trajectories substance disorders, phenome‐wide loci interest, pleiotropy, social genomics, nurture, within‐family comparisons. is one few genetics projects that includes substantial number participants African ancestry. The sharing data biospecimens has been cornerstone project, key contributor large‐scale GWAS consortia. wealth publicly available extensive unique adaptable resource our understanding traits.

Язык: Английский

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A critical review of ethanol effects on neuronal firing: A metabolic perspective

Alcohol Clinical and Experimental Research, Год журнала: 2024, Номер 48(3), С. 450 - 458

Опубликована: Янв. 12, 2024

Abstract Ethanol metabolism is relatively understudied in neurons, even though changes neuronal are known to affect their activity. Recent work demonstrates that ethanol preferentially metabolized over glucose as a source of carbon and energy, it reprograms neurons state reduced energy potential diminished capacity utilize once exhausted. intake has been associated with firing specific brain activity (EEG) patterns have linked risk for alcohol use disorder (AUD). Furthermore, haplotype the inwardly rectifying potassium channel subunit, GIRK2, which plays critical role regulating excitability AUD shown be directly regulated by ethanol. At same time, overexpression GIRK2 prevents ethanol‐induced metabolic changes. Based on available evidence, we conclude mechanisms underlying effects novel target developing therapies AUD.

Язык: Английский

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Whole Genome Sequencing of Pedigrees With High Density of Substance Use and Psychiatric Disorders: A Meeting Report

Genes Brain & Behavior, Год журнала: 2025, Номер 24(1)

Опубликована: Фев. 1, 2025

ABSTRACT The National Institute of Drug Abuse convened a panel scientists with expertise in substance use disorders (SUD) and genetic methodologies primarily to determine the feasibility performing whole genome sequencing utilizing existing pedigree collections high density SUD psychiatric disorders. A major focus was on determining if there had been any successes identifying variants for complex traits family‐based designs. Such information could provide assurance that might significant pay‐offs particularly pursuit rare copy number variants. An important goal discuss evaluate optimal strategies studying human samples. Specific topics were (a) consider whether smaller cases typically available family studies versus larger biobanks can reveal unique information; (b) identify potential gaps biobank data be supplemented data; (c) phenotypic definitions (e.g., quantity use, problem‐oriented) collection instruments (self‐report or clinician administered) are both practical efficient collect, likely insights concerning prevention, intervention, medication development. Conclusions reached by included optimism about have occurred ascertained include densely affected pedigrees. Evaluation led, overall, consensus steps should taken utilize conjunction investigations variant discovery.

Язык: Английский

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The collaborative study on the genetics of alcoholism: Brain function

Genes Brain & Behavior, Год журнала: 2023, Номер 22(5)

Опубликована: Авг. 17, 2023

Abstract Alcohol use disorder (AUD) and related health conditions result from a complex interaction of genetic, neural environmental factors, with differential impacts across the lifespan. From its inception, Collaborative Study on Genetics Alcoholism (COGA) has focused importance brain function as it relates to risk consequences alcohol AUD, through examination noninvasively recorded electrical activity neuropsychological tests. COGA's sophisticated neurophysiological measures, together rich longitudinal, multi‐modal family data, have allowed us disentangle brain‐related resilience factors prolonged heavy in context genomic social‐environmental influences over COGA led field identifying genetic variation associated functioning, which advanced understanding how affects AUD disorders. To date, study amassed data 9871 participants, 7837 at more than one time point, notable diversity terms age (from 7 97), gender (52% female), self‐reported race ethnicity (28% Black, 9% Hispanic). These are available research community several mechanisms, including directly NIAAA, dbGAP, collaboration investigators. In this review, we provide an overview collection methods specific measures assessed, showcase utility, significance, contributions these made our disorders, highlighting findings.

Язык: Английский

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Upregulated GIRK2 counteracts ethanol-induced changes in excitability & respiration in human neurons

Journal of Neuroscience, Год журнала: 2024, Номер unknown, С. e0918232024 - e0918232024

Опубликована: Фев. 13, 2024

Genome-wide association analysis (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified non-coding polymorphisms within the KCNJ6 gene. encodes GIRK2, a subunit G protein-coupled inwardly-rectifying potassium channel that regulates neuronal excitability. How changes in GIRK2 affect human excitability and response to repeated ethanol exposure is poorly understood. Here, we studied effect upregulating using an isogenic approach with glutamatergic neurons derived from induced pluripotent stem cells (male female donors). Using multi-electrode-arrays, population calcium imaging, single-cell patch-clamp electrophysiology, mitochondrial stress tests, find elevated acts concert 7-21 days inhibit activity, counteract ethanol-induced increases glutamate response, promote increase intrinsic Furthermore, prevented ethanol-dependent basal activity-dependent respiration. These data support role mitigating effects previously unknown connection function neurons. Significance Statement Alcohol major health problem worsened since COVID, affecting over 100 million people worldwide. While it known heritability contributes AUD, specific genes their remain understood, especially humans. In current manuscript, focused on which been AUD-endophenotype genome-wide study. We used excitatory healthy donors study impact expression. Our results reveal counteracts intracellular calcium, as well deficits The hyper-glutamatergic offers therapeutic promise treating AUD.

Язык: Английский

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Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels

Frontiers in Physiology, Год журнала: 2024, Номер 15

Опубликована: Июнь 6, 2024

Ion channels play a pivotal role in regulating cellular excitability and signal transduction processes. Among the various ion channels, G-protein-coupled inwardly rectifying potassium (GIRK) serve as key mediators of neurotransmission responses to extracellular signals. GIRK are members larger family inwardly-rectifying (Kir) channels. Typically, activated via direct binding G-protein βγ subunits upon activation receptors (GPCRs). channel requires presence lipid signaling molecule, phosphatidylinositol 4,5-bisphosphate (PIP

Язык: Английский

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5. Collaborative Study on the Genetics of Alcoholism: Functional genomics

Genes Brain & Behavior, Год журнала: 2023, Номер 22(5)

Опубликована: Авг. 2, 2023

Abstract Alcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors identified putative alcohol use disorder risk genes through genome‐wide association studies. In this review, we describe advances made by COGA in elucidating functional changes induced using multimodal approaches with human cell lines brain tissue. These studies involve gene regulation lymphoblastoid cells from participants post‐mortem tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms which alternate alleles differ driving expression. Specific (both coding or noncoding) have modeled pluripotent stem derived evaluate effects variants transcriptomics, neuronal excitability, synaptic physiology, response ethanol neurons individuals without disorder. We provide perspective future studies, such as polygenic scores populations cell‐derived signaling pathways related responses alcohol. Starting loci associated demonstrated that integration data within can reveal mechanisms linking genomic potential targets for treatments.

Язык: Английский

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