Ray, Anindita

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

AbstractBackgroundLewy body dementia (LBD) is the second most prevalent dementia in the United States after Alzheimer’s disease (AD). Recent studies have implicated rare mutations in two lipid transport genes, ABCA1 and ATP8B4, in Alzheimer’s disease. Substantial co‐pathology and shared risk factors indicate an intersectional genetic architecture between LBD and AD; therefore, we investigated the association of rare mutations in ABCA1 and ATP8B4 with LBD. Additionally, we examined rare mutations in 25 genes involved in ABCA1‐related lipid‐specific pathway with risk of developing LBD.MethodWe annotated rare missense and loss‐of‐function (LOF) mutations in ABCA1 and ATP8B4 genes, using Ensembl Variant Effect Predictor, in previously published whole‐genome sequence data from 2,591 LBD cases and 4,027 healthy controls of European ancestry. To test the association with LBD risk, we applied the optimized sequence kernel association test (SKAT‐O), followed by single‐variant association test (Fisher’s exact test), and multiple testing (Bonferroni correction). Additionally, we evaluated rare coding variants of 25 genes in ABCA1‐related positive regulation of the cholesterol efflux pathway (GO: 0010875) by performing single‐gene burden and gene‐set burden analyses.ResultsWe found a significant enrichment of rare ABCA1 missense mutations in LBD (SKAT‐O p = 2.68E‐02). However, no significant associations were found between LBD and ABCA1 LOF, and ATP8B4 LOF or missense mutations. Interestingly, the single‐variant analysis identified two ABCA1 missense variants, c.5398A>C; p.N1800H (Fisher’s test: p‐value = 1.16E‐04) and c.3544G>A; p.A1182T (p‐value = 4.29E‐02), with the p.N1800H substitution surviving Bonferroni multiple testing. The p.N1800H variant is reported to be pathogenic, and it was observed in twelve LBD patients and one control, with an odds ratio of 18.48 (95%CI = 2.4‐142.8). This mutation is reported to be pathogenic, in our LBD cohort, six out of twelve ABCA1 p.N1800H carriers also carry the APOE ε4 risk allele. However, neither a single‐gene burden nor a gene‐set burden analysis in 25 genes in the positive regulation of the cholesterol efflux pathway revealed any significant associations with LBD.ConclusionOur findings reveal significant enrichment of ABCA1 missense mutations in LBD emphasizing the genomic complexity surrounding LBD and AD.

AbstractBackgroundStructural variants range from simple loss or gain of genetic material to complex events that restructure entire chromosomes. This heterogeneity coupled with variant size greater than sequencing read‐length makes structural variant mapping from short‐read sequencing data difficult and error‐prone. Consequently, the role of structural variants is poorly explored in many phenotypes, including dementia.MethodWe used the GATK‐SV pipeline that combines four external structural variant mapping algorithms with machine‐learning to build high‐quality consensus structural variant calls. We applied GATK‐SV to short‐read whole‐genome sequencing data of 2,601 frontotemporal dementia‐amyotrophic lateral sclerosis spectrum (FTD/ALS) patients, 2,612 Lewy body dementia (LBD) patients, and 4,132 neurologically unaffected participants.ResultAfter stringent quality‐control, we performed genome‐wide association studies on 2,307 ALS/FTD patients versus 3,677 controls with 4,699 common structural variants and 2,355 LBD patients versus 3,700 controls with 4,889 common structural variants. In the FTD/ALS cohort, we identified well‐known risk variants at the C9orf72 (p‐value = 4.99×10‐18, OR = 14.47, 95% CI = 7.90–26.49) and MAPT loci (p‐value = 3.48×10‐6, OR = 0.77, 95% CI = 0.68–0.86) corroborating the ability of our pipeline to identify disease‐associated structural variants. Moreover, we discovered, replicated, and validated TPCN1 as a novel risk locus for LBD (p‐value = 9.18×10‐6, OR = 1.43, 95% CI = 1.22–1.67). Further, we identified rare exonic variants with known pathogenic or likely pathogenic effects, such as an SNCA gene duplication in LBD and a deletion of exons 1 and 2 in CHCHD10 in FTD/ALS. We additionally observed structural variants in regulatory regions, e.g. a deletion of a key PSEN2 enhancer, which resulted in an approximate 0.70 fold‐change in PSEN2 expression in LBD. Finally, we built an interactive web app where structural variants can be visualized and explored (https://ndru-ndrs-lng-nih.shinyapps.io/non_ad_dementias_sv_app/).ConclusionCommon and rare structural variants play a role in LBD and FTD/ALS. Our structural variant resource is publicly available and can be used to further explore the role of structural variants in LBD and FTD/ALS.