Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease

Background Simultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study. Methods We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. Results Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10−6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10−3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10−3) and visual (P = 5.6 × 10−4) cortices. Conclusions Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD

Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study

Comprehensivemetabolite profiling capturesmany highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serumamino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6million genotyped and imputed variants in 8545 nondiabetic Finnishmen fromtheMETabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966).We identified five novel loci associated with amino acid levels (P = < 5×10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10-26); ZFHX3 (chr16:73326579,minor allele frequency (MAF) = 0.42%, P = 3.6×10-9), LIPC (rs10468017, P = 1.5×10-8), and WWOX (rs9937914, P = 3.8×10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10-9). Gene-based tests identified two novel genes harboringmissense variants ofMAF < 1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5×10-6) and BCAT2 with valine (Pgene = 7.4×10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017,MAF=0.95%, Pconditional = 5.8×10-40) with glycine levels and HAL (rs141635447,MAF = 0.46%, Pconditional = 9.4×10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend < 0.001). These novel signals provide further insight into the molecularmechanisms of amino acidmetabolismand potentially, their perturbations in disease

Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers

More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10-2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Genome‐wide identification of modifiers of age‐at‐onset for Alzheimer’s disease in African American populations

Abstract Background Several studies have attempted to identify genes for age‐at‐onset (AAO) of Alzheimer’s disease (AD) through genome‐wide linkage and genome‐wide association studies (GWAS). While these efforts have thus far focused predominantly on non‐Hispanic white (NHW) populations, we present here the first GWAS to identify genetic contributors to AAO in African Americans (AA) using AA genotype and phenotype data from the Alzheimer’s Disease Genetics Consortium (ADGC). Method We combined data from 13 AA prospective and case‐control ADGC datasets, excluding family‐based datasets. Genotype data underwent standard quality control and were imputed to the TOPMed R5 reference panel using the Michigan Imputation Server. Data were merged across cohorts using QCTOOL and GTOOL, filtering out variants with MAF≤0.005). We performed two analyses: case‐only linear mixed‐model regression with AAO as outcome (LMM); and survival analysis using Cox proportional‐hazards frailty modeling (COXPHF) with time‐to‐AD‐onset (AAO in cases and censoring of controls at age‐at‐last‐exam). Both models were adjusted for sex, principal components capturing population substructure, and APOE‐ε4 dosage with a random cohort effect. Result We examined 2,262 AA AD cases, including 1,561 females (69%) with mean (SD) AAO of 77.7 (8.1) years. The APOE‐adjusted COXPHF analyses identified twelve genome‐wide significant regions (P0.05) in equivalent analyses in NHW ADGC cohorts (9,220 AD cases/10,350 controls; Li et al. Alz Dement 2023), except for the ABCA7 locus (NHW P<0.0002). Conclusion In a large ADGC African American dataset, we confirmed AAO associations in the APOE region and ABCA7 and observed evidence for potential novel AD AAO loci including SESTD1; many of which might be African‐ancestry specific

GWAS identifies genetic factors associated with severity of cerebral amyloid angiopathy pathology

Abstract Background Cerebral amyloid angiopathy (CAA) commonly co‐occurs with Alzheimer’s disease (AD) pathologies, leading to an increased risk and severity of cognitive decline. While CAA is known to impact cognitive impairment, the genetics of CAA are not well understood, and most previous sample sizes have been small. To address this gap, we conducted a genome‐wide association study (GWAS) of CAA pathology to identify genetic factors that are associated with this understudied AD‐related amyloidosis. Method We utilized data from 6,038 autopsied and genotyped individuals from the National Alzheimer’s Coordinating Centers (NACC) who were evaluated for CAA pathology upon autopsy. Participants were age 50+ at death and non‐Hispanic white. Genetic data were available from SNP arrays imputed to TOPMed and analyses were conducted only on common variants (MAF >0.01). GWAS performed ordinal logistic regression to determine the effects of genetic variants on CAA pathology (coded as 0, none; 1, mild; 2, moderate; 3, severe). Models adjusted for sex, age at death, and the first three genetic principal components (PC‐AiR; GENESIS; R v4.2). We then meta‐analyzed across the cohorts (METAL). Result We observed genome‐wide significant associations with CAA severity at established AD loci, including APOE (top SNP: rs429358, MAF = 0.155, P = 1.6E−86) and BIN1 (top SNP: rs6733839, MAF = 0.397, P = 3.9E−08). We observed a novel association with CAA pathology on chromosome 9 (top SNP: rs10908023, MAF = 0.258, P = 4.3E−11). Conclusion This is the largest study to date aimed at identifying genetics factors associated with CAA pathology. Our findings offer new insights into the genetics of CAA, a common player in the AD landscape. We acknowledge the need for a larger dataset and are now expanding the study by sample size and by including additional ADRD phenotypes to gain a better understanding of the full spectrum AD/ADRD. Continuing to uncover the genetic underpinnings of CAA could potentially help us think about AD treatment in new ways and mitigate the negative side‐effects of brain swelling and bleeding that have been observed in recent clinical trials