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Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci.

ABSTRACT: Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65-3.56, p-value = 7.0 × 10^-6) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10^-4). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer's-related risk for females with LBD.

SUBMITTER: Bayram E

PROVIDER: S-EPMC10879525 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci.

Bayram Ece E Reho Paolo P Litvan Irene I Ding Jinhui J Gibbs J Raphael JR Dalgard Clifton L CL Traynor Bryan J BJ Scholz Sonja W SW Chia Ruth R

NPJ Parkinson's disease 20240220 1

Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65-3.56, p-value = 7.0 × 10<sup>-6</ ...[more]

PMID: 38378815

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Project description:BackgroundThe current genome-wide association study (GWAS) of Lewy body dementia (LBD) suffers from low power due to a limited sample size. In addition, the genetic determinants underlying LBD and the shared genetic etiology with Alzheimer's disease (AD) and Parkinson's disease (PD) remain poorly understood.MethodsUsing the largest GWAS summary statistics of LBD to date (2591 cases and 4027 controls), late-onset AD (86,531 cases and 676,386 controls), and PD (33,674 cases and 449,056 controls), we comprehensively investigated the genetic basis of LBD and shared genetic etiology among LBD, AD, and PD. We first conducted genetic correlation analysis using linkage disequilibrium score regression (LDSC), followed by multi-trait analysis of GWAS (MTAG) and association analysis based on SubSETs (ASSET) to identify the trait-specific SNPs. We then performed SNP-level functional annotation to identify significant genomic risk loci paired with Bayesian fine-mapping and colocalization analysis to identify potential causal variants. Parallel gene-level analysis including GCTA-fastBAT and transcriptome-wide association analysis (TWAS) was implemented to explore novel LBD-associated genes, followed by pathway enrichment analysis to understand underlying biological mechanisms.ResultsPairwise LDSC analysis found positive genome-wide genetic correlations between LBD and AD (rg = 0.6603, se = 0.2001; P = 0.0010), between LBD and PD (rg = 0.6352, se = 0.1880; P = 0.0007), and between AD and PD (rg = 0.2136, se = 0.0860; P = 0.0130). We identified 13 significant loci for LBD, including 5 previously reported loci (1q22, 2q14.3, 4p16.3, 4q22.1, and 19q13.32) and 8 novel biologically plausible genetic associations (5q12.1, 5q33.3, 6p21.1, 8p23.1, 8p21.1, 16p11.2, 17p12, and 17q21.31), among which APOC1 (19q13.32), SNCA (4q22.1), TMEM175 (4p16.3), CLU (8p21.1), MAPT (17q21.31), and FBXL19 (16p11.2) were also validated by gene-level analysis. Pathway enrichment analysis of 40 common genes identified by GCTA-fastBAT and TWAS implicated significant role of neurofibrillary tangle assembly (GO:1902988, adjusted P = 1.55 × 10-2).ConclusionsOur findings provide novel insights into the genetic determinants of LBD and the shared genetic etiology and biological mechanisms of LBD, AD, and PD, which could benefit the understanding of the co-pathology as well as the potential treatment of these diseases simultaneously.

Project description:Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

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Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci.

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Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci.

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