New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Dissecting the role of Amerindian genetic ancestry and ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population

Abstract Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. ApoE ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic White populations and has a relatively lower effect in African descent populations. Admixture analysis in the African American and Puerto Rican populations showed that the variation in ε4 risk is correlated with the genetic ancestral background local to the ApoE gene. Native American populations are substantially underrepresented in AD genetic studies. The Peruvian population with up to ∼80 of Amerindian ancestry provides a unique opportunity to assess the role of Amerindian ancestry in Alzheimer disease. In this study we assess the effect of the ApoE ε4 allele on AD in the Peruvian population. A total of 78 AD cases and 128 unrelated cognitive healthy controls were included in the study. Genome-wide genotyping was performed using the Illumina Global screening array. Global ancestry and local ancestry analyses were assessed. The effect of the ApoE ε4 allele on Alzheimer disease was tested using a logistic regression model by adjusting for age, gender, and population substructure (first three principal components). Logistic regression results showed that ApoE ε4 allele is significantly associated with AD in Peruvian population with the high-risk effect (OR = 5.02, CI: 2.3-12.5, p-value = 2e-4). The average values of the local ancestries surrounding the ApoE gene (chr19:44Mb-46Mb) have the highest proportion of Amerindian (60.6%), followed by European (33.9%) and African (5.5%) ancestral backgrounds. Our results showed that the risk for AD from ApoE ε4 in Peruvians is higher than we have observed in non-Hispanic White populations. Given the high admixture of Amerindian ancestry in the Peruvian population, it suggests that the Amerindian local ancestry is contributing to a strong risk for AD in ApoE ε4 carriers. Our data also support the findings of an interaction between the genetic risk allele ApoE ε4 and the ancestral backgrounds located around the genomic region of ApoE gene

Correction: Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

A correction to this paper has been published and can be accessed via a link at the top of the paper

Linkage Analysis in Caribbean Hispanic Families with Puerto Rican Ancestry Idenitfies an Alzheimer Disease Locus on chromosome 9

Abstract Background The ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to the discovery of ancestry-specific genetic factors in Alzheimer disease. In this study, we performed whole genome sequencing in multiplex Caribbean Hispanic Puerto Rican families to identify rare causal variants influencing Alzheimer disease through linkage and segregation-based approaches. Methods As part of the Puerto Rican Alzheimer Disease Initiative, whole genome sequencing data were generated for 100 individuals (61 affected) from 23 Puerto Rican families. To identify the genetic loci likely to carry risk variants, we performed a parametric multipoint affected individuals-only linkage analysis using MERLIN software. Following the linkage analysis, we identified the consensus region (heterogeneity logarithm of the odds score (HLOD) > 5.1), annotated variants using Ensembl Variant Effect Predictor, and combined annotation dependent depletion score (CADD). Finally, we prioritized variants according to allele frequency ( 10), and complete segregation among affected individuals. Results A locus at 9p21 produced a linkage HLOD score of 5.1 in the parametric affecteds-only multipoint affected individuals-only model supported by 9 families. Through the prioritization step, we selected 36 variants (22 genic variants). Candidate genes in the regions include C9orf72, UNC13B , and ELAVL2 . Conclusions Linkage analysis of Caribbean Hispanics Puerto Rican families confirmed previously reported linkage to 9p21 in non-Hispanic White and Israeli-Arap families. Our results suggest several candidates in the region as conferring AD risk. Identified putative damaging rare variants in multiplex families indicates the critical role of rare variation in Alzheimer disease etiology

Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (P<0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD