A locus at 19q13.31 significantly reduces the <em>ApoE</em> ε4 risk for Alzheimer\u27s Disease in African Ancestry

Copyright: \ua9 2022 Rajabli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the “protective” direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention

A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease

Introduction The genetic architecture of Alzheimer's disease (AD) is only partially understood. Methods We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome–sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. Results We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10−10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10−10). Discussion Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.</p

Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease

Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent. We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O. Analysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L missense variant (rs28709356; minor allele frequency = 0.002; P = 7.3 × 10 ) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10 ). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10 ). The expression of TAMM41 was lower in AD cases than controls (P = .00046) or mild cognitive impairment cases (P = .03). Significant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD

A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease

Introduction: The genetic architecture of Alzheimer's disease (AD) is only partially understood. Methods: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome–sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. Results: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10 −10 ) which improved when combined with results from stage 2 data sets (P = 1.92 × 10 −10 ). Discussion: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study

Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans

This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions. We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes. Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10 ) and 18q21.33 (p = 1.2 × 10 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2. Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus. We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations

Large‐scale sequencing studies expand the known genetic architecture of Alzheimer's disease

Introduction Genes implicated by genome‐wide association studies and family‐based studies of Alzheimer's disease (AD) are largely discordant. We hypothesized that genes identified by sequencing studies like the Alzheimer's Disease Sequencing Project (ADSP) may bridge this gap and highlight shared biological mechanisms. Methods We performed structured literature review of genes prioritized by ADSP studies, genes underlying familial dementias, and genes nominated by genome‐wide association studies. Gene set enrichment analyses of each list identified enriched pathways. Results The genes prioritized by the ADSP, familial dementia studies, and genome‐wide association studies minimally overlapped. Each gene set identified dozens of enriched pathways, several of which were shared (e.g., regulation of amyloid beta clearance). Discussion Alternative study designs provide unique insights into AD genetics. Shared pathways enriched by different genes highlight their relevance to AD pathogenesis, while the patterns of pathway enrichment unique to each gene set provide additional targets for functional studies