Genetic Architecture Of Alzheimer's Disease Research Articles

A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease

AbstractBackgroundIncreasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian (PE) population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We performed the first genome‐wide association study (GWAS) in the PE population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.MethodThe PE dataset includes array‐genotype and phenotype data from 542 individuals (189 cases; 353 controls), imputed to the NHLBI TOPMedv5 haplotype reference panel. We used a generalized linear mixed‐model (SAIGE software) for the GWAS analysis. We analyzed two separate models; the first model accounted for sex, age, and population substructure, while the second model also included the dosage of APOEe4. In both models, we included a genetic relationship matrix as a random effect to account for any potential relatedness. To determine if the associations are specific to specific ancestries, we employed ancestry‐aware approaches using the RFMix software.ResultAPOE was significantly associated with AD with an effect size comparable to that found in non‐Hispanic white (NHW) populations (OR = 3.3(2.2‐4.8),pv = 8.0×10−10). Two additional known AD loci, TREML2 (pv = 0.008) and CLU (pv = 0.012), showed nominal significance Variants at three additional loci reached suggestive significance (pv<1×10−6): NFASC (pv = 9.4×10−8;chromosome 1), STK32A (pv = 9.3×10−7; chromosome 5), and LOC100132830 (pv = 6.7×10−7;chromosome 6). The NFASC locus neared genome‐wide significance in the APOE adjusted model (pv = 6.7×10−8). The haplotypes associated with AD at the NFASC locus were found to be of European origin. Additionally, the STK32A locus was found to have a protective effect specifically among individuals of AI background. We did not observe significant heterogeneity of effect at the APOE and LOC100132830 loci across different ancestral backgrounds.ConclusionPE GWAS identified a novel, promising AD susceptibility locus in the NFASC gene of European origin. We also detected a potential protective effect in the STK32A locus on AI background, emphasizing the importance of incorporating ancestry‐aware approaches in gene discovery in admixed populations.

Association Between Episodic Memory and Genetic Risk Factors for Alzheimer's Disease in South Asians from the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD).

Genetic factors play an important role in Alzheimer's disease (AD) and cognitive aging. However, it is unclear whether risk loci identified in European ancestry (EA) populations have similar effects in other groups, such as South Asians. We investigated the allelic distribution and cognitive associations of 56 known AD risk single-nucleotide polymorphisms (SNPs) identified from three EA genome-wide association studies (EA-GWASs) in a South Asian population. Single SNP and genetic risk score (GRS) associations with measures of episodic memory were assessed. The Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). A total of 906 LASI-DAD participants from diverse states in India. Participants were genotyped using the Illumina Global Screening Array and imputed with 1000G Phase 3v5. Cognitive measures included total learning and delayed word recall. Although only a few SNPs were significantly associated with memory scores (P < .05), effect estimates from the EA-GWAS and the LASI-DAD showed moderate correlation (0.35-0.88) in the expected direction. GRSs were also associated with memory scores, although percentage variation explained was small (0.1%-0.6%). Discrepancies in allele frequencies and cognitive association results suggest that genetic factors found predominantly through EA-GWASs may play a limited role in South Asians. However, the extent of differences in the genetic architecture of AD and cognition in EA and South Asians remains uncertain. There is also a critical need to perform a more comprehensive assessment of the mutational spectrum of South Asia to identify novel genetic variants associated with AD and cognition in this population. J Am Geriatr Soc 68:S45-S53, 2020.

THE CONTRIBUTION OF SEX-SPECIFIC ASSOCIATIONS IN GENETIC STUDIES OF ALZHEIMER’S DISEASE PATHOLOGY

Women are disproportionately affected by Alzheimer's disease (AD) and more likely to manifest clinical symptoms in the presence of AD neuropathology. Yet, sex differences are often ignored or modeled as a nuisance variable in genetic association studies of AD. We performed comprehensive sex-specific genetic analyses of AD biomarkers and autopsy measures of AD neuropathology to evaluate whether sex-specific genetic effects contribute to AD pathogenesis. First we performed a sex-stratified GWAS in 5,978 participants with autopsy measures of neurofibrillary tangles (Braak staging) and neuritic plaques (CERAD score). Then we used the innovative UTMOST (Unified Test for MOlecular SignaTures) method in 3,119 participants with CSF measures of Aβ42 and total tau to test for sex-specific associations with predicted gene expression. In these participants, gene expression profiles were jointly imputed in 44 tissues available in GTEx. Cross-tissue gene-level association results for 14,709 genes were then constructed using a generalized Berk-Jones test. Bonferroni-corrected significance thresholds for GWAS and UTMOST analyses were α=5.0x10−8 and α=3.4x10−6, respectively. In the GWAS, rs34331204 (intergenic; 7p21.1; MAF=0.07) was associated with presence of tangles in males (β=-0.74, p=9.1x10−9) but not females (β=-0.03, p=0.85). In the UTMOST analysis, we found a female-specific association between predicted expression of KLDR1 and CSF Aβ42 (pmales=0.13; pfemales=2.4x10−6). Male-specific associations were found for predicted expressions of PPP2R1B with CSF Aβ42 (pmales=1.5x10−7; pfemales=0.81) and NOTCH3 with CSF tau (pmales=5.6x10−7; pfemales=0.62). Results highlight how sex differences can enhance our understanding of the molecular basis and genetic architecture of AD. Among females, we identified KLDR1, an inhibitor of natural killer cells. This female-specific role of innate immunity is consistent with our previous findings. Among males, we identified rs34331204, a cis eQTL for BZW2 (BRAINEAC aveALL p=1.9x10−5), which has been implicated in neuronal differentiation. Additionally, we identified NOTCH3 and PPP2R1B, a regulatory subunit of PP2A, which are involved in Notch and Wnt signaling cascades. Combined with our past results, these findings suggest the innate immune pathway may be particularly relevant to AD pathogenesis in females, while the neurogenesis pathway may be particularly relevant in males. Future work will functionally assess these sex-specific candidate genes.

Transethnic genome-wide scan identifies novel Alzheimer's disease loci

IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10−6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10−6). DiscussionOur findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Pinpointing key mechanisms in Alzheimer's disease development

van Exel and colleagues present an elegant study testing relationships between vascular and inflammatory traits and the risk of Alzheimer's disease (AD) development. They compared middle-aged offspring of AD cases with similar offspring of nondemented parents and observed greater inflammatory response to challenge and increased hypertension in those at high genetic risk. These observations join a growing body of evidence implicating inflammation/innate immunity as a crucial component in disease development. Recent discoveries of new risk genes for Alzheimer's disease also implicate innate immunity and to some extent vascular health as potentially important in pathogenesis. Further identification and refinement of putative disease mechanisms is likely as the genetic architecture of AD is uncovered through current large-scale association and sequencing studies.