Journal of neurogenetics最新文献

{"title":"Neurocardiogenetics: Exploring the association of rare <i>RYR2</i> variants with neuropsychiatric disorders in general and disease populations.","authors":"Saif F Dababneh, Jason D Roberts, Sixuan Tan, Jinhong Wei, Ruiwu Wang, John Paul Estillore, Dania Kallas, Glen F Tibbits, Shubhayan Sanatani, S R Wayne Chen, Thomas M Roston","doi":"10.1080/01677063.2026.2632080","DOIUrl":"10.1080/01677063.2026.2632080","url":null,"abstract":"<p><p>Overlapping neuropsychiatric and cardiac features in rare monogenic syndromes stem from shared gene expression. Pathogenic gain-of-function <i>RYR2</i> variants, leading to a lethal cardiac arrhythmia syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT), have also been associated with neuropsychiatric disorders such as epilepsy, schizophrenia, and intellectual disability. Neuropsychiatric phenotypes have not been reported in patients with calcium release deficiency syndrome (CRDS), a recently described inherited arrhythmia disorder distinct from CPVT caused by loss-of-function <i>RYR2</i> variants. Whether there is a robust association between ultra-rare <i>RYR2</i> variants and neuropsychiatric phenotypes in large population databases and disease cohorts has not been determined to-date. Here, we explore the association of <i>RYR2</i> variants with neuropsychiatric disorders in 748,879 individuals from multiple biobanks, including 155,236 non-Europeans, and in neuropsychiatric disease cohorts. Our analyses suggest an association between <i>RYR2</i> variants and epilepsy, while links with other disorders were not robust. In this process, a previously uncharacterized <i>RYR2</i> variant (p.Y4962N) with conflicting reported pathogenicity was found to be associated with both cardiac and neuropsychiatric phenotypes. To better understand the potential impact of the variant, we further assessed its mechanistic impact and found that RyR2<i>-</i>p.Y4962N results in loss-of-function. Such a finding has not been reported previously in association with <i>RYR2</i> loss-of-function variants or CRDS. Altogether, our study expands our understanding of the involvement of <i>RYR2</i> variants in neurocardiac phenotypes in general populations and disease cohorts, which could enhance personalized medicine efforts by integrating cardiac and neuropsychiatric risk profiles.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"86-94"},"PeriodicalIF":1.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147290146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of sulfate pathway genes in human neurodevelopment.","authors":"Prasidhee Vijayakumar, Kim M Summers, Paul A Dawson","doi":"10.1080/01677063.2026.2649162","DOIUrl":"10.1080/01677063.2026.2649162","url":null,"abstract":"<p><p>Sulfate is a vital nutrient for healthy brain development. More than 90 sulfate-related genes are highly conserved across mammalian species, with 16 of these genes being clinically reportable for adverse brain conditions. To determine the potential involvement of additional sulfate-related genes in human neuropathology, this study curated the spatial and temporal expression patterns of all known sulfate biology genes in the human fetal brain from 8 to 37 post conception weeks (pcw) using data from the BrainSpan database and performed network analysis to cluster sulfate-related genes with genes involved in neurodevelopmental processes. A total of 64 sulfate-related genes were abundantly or moderately expressed in 11 brain regions throughout gestation. Steady state expression was observed for some of these genes from 8 to 37 pcw, including genes that encode sulfotransferases (<i>CHST12</i>, <i>CHST7</i>), sulfatases (<i>ARSA</i>, <i>SULF2</i>, <i>TPST1</i>, <i>TPST2</i>), sulfatase modifying enzyme (<i>SUMF2</i>), key enzymes in amino acid metabolism (<i>CDO1</i>, <i>CTH</i>), sulfate transporter (<i>SLC26A11</i>), as well as genes involved in neurodevelopmental processes (<i>ACTG1</i>, <i>TUBA1A</i>, <i>MAPT</i>, <i>UBE3A</i>, <i>DCHS1</i>, <i>WWOX</i>). Between 21-24 weeks, there were numerous clusters of sulfate biology genes with neurodevelopmental genes involved in neuronal migration (<i>FAT4)</i> and synaptogenesis (<i>CBLN2</i>, <i>WNT4</i>, <i>MAPT</i>, <i>FOXP2</i>). At 8-13 and 17-21 pcw, fifteen sulfate genes (<i>ARSF</i>, <i>CHST1</i>, <i>CHST2</i>, <i>CHST13</i>, <i>GAL3ST3</i>, <i>GOT1</i>, <i>IDS</i>, <i>HS3ST2</i>, <i>HS3ST4</i>, <i>HS6ST3</i>, <i>SLC26A8</i>, <i>STS</i>, <i>SULT1A1</i>, <i>SULT4A1</i>, <i>UST</i>) were expressed in the hippocampus and clustered with genes involved in neurogenesis, differentiation and synaptogenesis (<i>MAPT</i>, <i>DNER</i>, <i>NEUROD1</i>). Overall, this study identified 48 sulfate-related genes with moderate/abundant expression in the fetal brain that are coexpressed with genes for neurodevelopmental processes but are not considered in clinical settings. These findings provide information for future studies into the physiological roles of sulfate-related genes that are expressed in the fetal brain.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"60-79"},"PeriodicalIF":1.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbial metabolites link dietary history to appetite regulation.","authors":"Emma C Spillman, Andrew K Shepherd, Meihua C Kuang, In-Hwan Jang, Won-Jae Lee, Jing W Wang","doi":"10.1080/01677063.2025.2548783","DOIUrl":"10.1080/01677063.2025.2548783","url":null,"abstract":"<p><p>All metazoan guts harbor commensal communities, from a dozen bacterial species in <i>Drosophila</i> to hundreds in humans. Here, we condition flies with diets containing varying levels of protein and sugar to investigate the impact of dietary history on the interaction between commensal gut bacteria and feeding adaptation in <i>Drosophila</i>. We find that appetite increases with dietary protein, dependent on total gut bacteria content, and enhanced by a drug that promotes the growth of short-chain fatty acid (SCFA)-producing gut bacteria. <i>Lactiplantibacillus</i> is a potential source of butyrate, while <i>Acetobacter</i> produces acetate. Mono-association with <i>Acetobacter</i> or <i>Lactiplantibacillus</i> increases food intake. Mutant strains unable to produce acetate or butyrate have lesser effects. Finally, adding acetate or butyrate to conditioning diets recapitulates the appetitive effect of <i>Acetobacter</i> and <i>Lactiplantibacillus</i>, respectively. Our findings suggest that protein-enriched diets enhance appetite by promoting the interaction between commensal bacteria and the host, with bacterial SCFAs as a conduit.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"85-94"},"PeriodicalIF":1.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12925084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous recording of spikes and calcium signals in odor-evoked responses of <i>Drosophila</i> antennal neurons.","authors":"Yiyi Xiao, Shiuan-Tze Wu, Yinan Xuan, Scott A Rifkin, Chih-Ying Su","doi":"10.1080/01677063.2025.2561596","DOIUrl":"10.1080/01677063.2025.2561596","url":null,"abstract":"<p><p>Most insects, including agricultural pests and disease vectors, rely on olfaction for key innate behaviors. Consequently, there is growing interest in studying insect olfaction to gain insights into odor-driven behavior and to support efforts in vector control. Calcium imaging using GCaMP fluorescence is widely used to identify olfactory receptor neurons (ORNs) responsive to ethologically relevant odors. However, accurate interpretation of GCaMP signals in the antenna requires understanding both response uniformity within an ORN population and how calcium signals relate to spike activity. To address this, we optimized a dual-modality recording method combining single-sensillum electrophysiology and widefield imaging for <i>Drosophila</i> ORNs. Calcium imaging showed that homotypic ab2A neurons exhibit similar odor sensitivity, consistent with spike recordings, indicating that a single ORN's response can reliably represent its homotypic counterparts. Furthermore, concurrent dual recordings revealed that peak calcium responses are linearly correlated with spike activity, regardless of imaging site (soma or dendrites), GCaMP variant, odorant, or fly age. These findings validate the use of somatic calcium signals as a reliable proxy for spike activity in fly ORNs and provide a foundation for future large-scale surveys of spike-calcium response relationships across diverse ORN types.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"105-115"},"PeriodicalIF":1.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13088990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic convergence in brain aging and neurodegeneration: from cellular mechanisms to therapeutic targets.","authors":"Polu Picheswara Rao, Shubham Mishra","doi":"10.1080/01677063.2025.2571127","DOIUrl":"10.1080/01677063.2025.2571127","url":null,"abstract":"<p><p>The distinction between normal brain aging and neurodegeneration has traditionally been viewed as a binary classification, yet emerging evidence reveals a complex continuum of shared genetic mechanisms underlying both processes. This review synthesises current understanding of conserved molecular pathways that contribute to age-related neural decline across the spectrum from healthy aging to pathological neurodegeneration. We examine how fundamental cellular processes including protein quality control, mitochondrial dysfunction, inflammation, and synaptic maintenance are genetically regulated and become progressively dysregulated during aging. Key genetic pathways, such as insulin/IGF signalling, autophagy-lysosomal networks, and stress response mechanisms demonstrate remarkable conservation from model organisms to humans, suggesting evolutionary constraints on neural aging processes. The review highlights how genetic variants in these pathways can determine individual trajectories along the aging-neurodegeneration continuum, influencing susceptibility to diseases like Alzheimer's, Parkinson's, and ALS. We discuss evidence from comparative studies in <i>C. elegans</i>, Drosophila, rodents, and human populations that illuminate shared vulnerability genes and protective factors. Understanding these convergent mechanisms offers unprecedented opportunities for therapeutic intervention, as strategies targeting fundamental aging processes may simultaneously address multiple neurodegenerative conditions. This integrated perspective challenges traditional disease-centric approaches and supports the development of unified therapeutic strategies for promoting healthy brain aging while preventing neurodegeneration.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"140-159"},"PeriodicalIF":2.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of whole genome sequence data shows association of Alzheimer's disease with rare coding variants in <i>ABCA7</i>, <i>PSEN1</i>, <i>SORL1</i> and <i>TREM2</i>.","authors":"David Curtis, Shujaani Joseph","doi":"10.1080/01677063.2025.2561589","DOIUrl":"10.1080/01677063.2025.2561589","url":null,"abstract":"<p><p>Previous studies have reported associations between risk of Alzheimer's disease (AD) or dementia and rare coding variants in a number of genes. A two-stage strategy was used in which a previously released whole exome sequenced sample was used to prioritise 100 genes showing the strongest evidence for association with AD. These genes were then analysed in a newly released whole genome sequenced sample to identify those which showed statistically significant evidence for rare coding variant association. Association analysis of loss of function (LOF) and nonsynonymous variants was carried out in 18,998 protein-coding genes using 11,188 controls and 5,808 cases, with nonsynonymous variants being annotated using 45 different pathogenicity predictors. The 100 genes showing strongest evidence for association were then analysed in a new sample of 27,749 controls and 13,234 cases using only the pathogenicity predictor which had performed best in the first sample. Four genes were statistically significant after correction for multiple testing: <i>ABCA7</i>, <i>PSEN1</i>, <i>SORL1</i> and <i>TREM2</i>. The association of different categories of variant with AD was characterised and the pattern was seen to vary between genes. This study quantifies the contribution of different types of variant within each gene to AD risk. In general, these variants are probably too rare to be clinically useful for assessing individual risk of AD. Further research into the mechanisms whereby the products of these genes affect AD pathogenesis may aid development of novel therapeutic strategies.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"95-104"},"PeriodicalIF":2.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A cell-autonomous role for the vitamin B6 metabolism gene <i>PNPO</i> in <i>Drosophila</i> GABAergic neurons.","authors":"Wenqin Fu, Saul Landaverde, Xiaoxi Zhuang, Atulya Iyengar","doi":"10.1080/01677063.2025.2591617","DOIUrl":"10.1080/01677063.2025.2591617","url":null,"abstract":"<p><p>In animals, the enzyme pyridox(am)ine 5'-phosphate oxidase (PNPO) is critical for synthesizing the active form of vitamin B6 (VB6), pyridoxal 5'-phosphate (PLP), from inactive vitamers. PLP is a required cofactor for many enzymatic reactions, including the synthesis of GABA and the monoamines. <i>PNPO</i> disruption in humans is associated with an array of epilepsy syndromes, while <i>Drosophila</i> harboring mutations in the sole <i>PNPO</i> ortholog, <i>sugarlethal</i> (<i>sgll</i>), display spontaneous seizures and shortened lifespans. These phenotypes are suppressed by PLP dietary supplementation and are exacerbated by restriction of dietary B6 vitamers. In the context of PNPO deficiency, it remains to be resolved what the specific contributions by cellular subpopulations in the nervous system are to the neurological phenotypes. We addressed this question in <i>sgll</i> mutants by expressing human <i>PNPO</i> (<i>hPNPO</i>) cDNA in cholinergic, glutamatergic, and GABAergic neurons as well as glia and measuring changes in survival and seizure phenotypes. We found <i>hPNPO</i> expression in GABAergic neurons largely restored lifespan and attenuated seizure activity, while glial expression also improved <i>sgll</i> phenotypes albeit to a lesser degree. In contrast, <i>hPNPO</i> expression in either cholinergic or glutamatergic neurons, accounting for most neurons in the fly brain, did not appreciably alter <i>sgll</i> phenotypes. We contrasted these observations with changes in <i>sgll</i> mutants induced by feeding GABA receptor modulators. The GABA_B agonist SKF-97541 reduced mortality, while GABA or GABA_A receptor modulators did not improve survival. Together, our data establish a cell-autonomous role for PNPO in GABAergic neurons to support brain function, especially under VB6-restricted conditions.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"126-133"},"PeriodicalIF":1.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conservation and diversification of mating behavior patterns among three sibling species in the <i>Drosophila subobscura</i> species subgroup.","authors":"Kenta Tomihara, Ryoya Tanaka, Francisco Rodríguez-Trelles, Daisuke Yamamoto","doi":"10.1080/01677063.2025.2567865","DOIUrl":"10.1080/01677063.2025.2567865","url":null,"abstract":"<p><p>Behavioral traits are known to evolve rapidly, often even preceding morphological or physiological changes. However, the genomic and neural bases for such rapid behavioral changes remain to be clarified. <i>Drosophila subobscura</i> is a rare example of a species that performs nuptial gift giving, while the mating behaviors of the other two members of the <i>subobscura</i> species subgroup, <i>D. madeirensis</i> and <i>D. guanche</i>, remain largely unstudied. In the present study, we characterize and compare mating behaviors of three sibling species of the <i>subobscura</i> species subgroup, with the aim of providing a starting point for investigating the neural mechanisms underlying reproductive behavioral divergence in the <i>subobscura</i> subgroup. We find that <i>D. madeirensis</i> males exhibit a rich repertoire of courtship behaviors-very similar to that of <i>D. suboscura</i>-including tapping, midleg swinging, proboscis extension and nuptial gift giving. In contrast, <i>D. guanche</i> males perform only tapping and lack the other premating displays, yet they still copulate successfully. We postulate that female promiscuity has promoted the loss of multiple components of the male courtship repertoire in <i>D. guanche</i>. The relatively recent divergence among these species (∼1.72 Myr between <i>D. guanche</i> and other two species) suggests that only a few genomic and neural changes underpin the striking differences in mating behavior within the <i>subobscura</i> species subgroup. This system offers a promising platform for uncovering the mechanistic basis of rapid behavioral evolution.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"116-125"},"PeriodicalIF":2.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum LncRNA XIST and miR-133b as non-invasive biomarkers for diagnosis and progression of Parkinson's disease.","authors":"Weihua Rao, Yanqiong Qin","doi":"10.1080/01677063.2025.2591630","DOIUrl":"10.1080/01677063.2025.2591630","url":null,"abstract":"<p><p>Long non-coding RNA XIST (LncRNA XIST) and microRNA-133b (miR-133b) have been implicated in Parkinson's disease (PD)-related pathophysiology and may serve as potential circulating biomarkers. The aim of this study was to study the serum expression levels of LncRNA XIST and miR-133b in PD patients and healthy controls, assess their correlation with disease severity, and evaluate their diagnostic value. Peripheral blood was obtained from 63 patients with PD and 21 healthy controls. Serum RNA was extracted, and the expression of LncRNA XIST and miR-133b was measured. PD severity was determined through standardized neurological evaluation, incorporating the Unified Parkinson's Disease Rating Scale (UPDRS) for symptom burden and the Hoehn and Yahr (H&Y) scale for disease staging. Serum LncRNA XIST levels were significantly higher in PD patients compared with controls, whereas miR-133b levels were significantly lower. LncRNA XIST positively correlated with UPDRS total score (<i>r</i> = .279, <i>p</i> = .027) and H&Y stage (<i>r</i> = .926, <i>p</i> < .001), while miR-133b showed a strong negative correlation with H&Y stage (<i>r</i> = -.957, <i>p</i> < .001). Receiver operating characteristic analysis revealed that LncRNA XIST had an area under the curve (AUC) of 0.824, miR-133b had an AUC of 0.787, and the combined model yielded an AUC of 0.807. The combined model performed better than miR-133b alone but slightly lower than LncRNA XIST alone. Serum LncRNA XIST and miR-133b are significantly altered in PD and strongly associated with disease stage. Both biomarkers demonstrate good diagnostic performance, and their combined use may provide complementary information for PD diagnosis and monitoring.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"134-139"},"PeriodicalIF":2.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of 470,000 exome-sequenced UK biobank participants identifies genes containing rare variants which confer dementia risk.","authors":"Lily Gibbons, David Curtis","doi":"10.1080/01677063.2025.2522643","DOIUrl":"10.1080/01677063.2025.2522643","url":null,"abstract":"<p><p>Previous studies have reported that rare coding variants in a handful of genes have major effects on risk of Alzheimer's disease (AD). A recent exome wide association study (ExWAS) of dementia in a subset of the UK Biobank cohort implicated a number of genes, including five which were novel. Here we report a similar analysis, carried out on the full cohort of 470,000 exome-sequenced participants. A score was assigned to each participant depending on individual and/or parental diagnosis of dementia. Regression analysis including <i>APOE</i> ε3 and ε4 doses as covariates was applied to gene-wise tests for association with loss of function (LOF) and nonsynonymous variants. 45 tests using different pathogenicity predictors were applied to the first cohort of 200,000 participants. Subsequently the 100 genes showing strongest evidence for association were analysed in the second cohort of 270,000 participants, using only the best-performing predictor for each gene. Three genes achieved statistical significance, <i>TREM2</i>, <i>SORL1</i> and <i>ABCA7</i>. The five genes reported as novel in the ExWAS did not produce any appreciable evidence for association in this study. The effects and frequencies of variants in different functional categories were characterised for these genes. Rare coding variants in a small number of genes have important effects on dementia risk. Further study of individual variant effects might elucidate mechanisms of pathogenesis. Incorporating rare variant effects for individual risk assessment might become important if preventative treatments for dementia become available. This research has been conducted using the UK Biobank Resource.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"77-84"},"PeriodicalIF":2.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}