Importance: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts.
Objective: To determine the frequency of genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to middle-aged (ages 50-64), old (ages 65-79), and oldest-old (ages 80+) controls and Alzheimer's disease (AD) dementia cases.
The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's Disease and Related Dementias (AD/ADRD) by sequencing whole genomes of affected participants and age-matched cognitive controls from diverse populations. The Genome Center for Alzheimer's Disease (GCAD) processed whole-genome sequencing data from 36,361 ADSP participants, including 35,014 genetically unique participants of which 45% are from non-European ancestry, across 17 cohorts in 14 countries in this fourth release (R4). This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 2.
View Article and Find Full Text PDFNIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimer's Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples.
View Article and Find Full Text PDFProgressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored.
View Article and Find Full Text PDFAlzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO).
View Article and Find Full Text PDFRich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort.
View Article and Find Full Text PDFIntroduction: Transcriptome-wide Association Studies (TWAS) extend genome-wide association studies (GWAS) by integrating genetically-regulated gene expression models. We performed the most powerful AD-TWAS to date, using summary statistics from -eQTL meta-analyses and the largest clinically-adjudicated Alzheimer's Disease (AD) GWAS.
Methods: We implemented the OTTERS TWAS pipeline, leveraging -eQTL data from cortical brain tissue (MetaBrain; N=2,683) and blood (eQTLGen; N=31,684) to predict gene expression, then applied these models to AD-GWAS data (Cases=21,982; Controls=44,944).
Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.
View Article and Find Full Text PDFThe heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits.
View Article and Find Full Text PDFIntroduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.
Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts.
Results: We found high heritability for two ancestry backgrounds.
Background: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear.
Methods: We conducted the largest sex-aware genetic study on late-life memory to date (N = 11,942; N = 15,641).
Alzheimer's Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or near , , and significantly associated with AD (p < 5×10).
View Article and Find Full Text PDFBackground: The X chromosome is often omitted in disease association studies despite containing thousands of genes which may provide insight into well-known sex differences in the risk of Alzheimer's Disease.
Objective: To model the expression of X chromosome genes and evaluate their impact on Alzheimer's Disease risk in a sex-stratified manner.
Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data.
Background: Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2.
Methods: HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512).
Introduction: Our understanding of the genetic predisposition for age-at-onset (AAO) of Alzheimer's disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any have sex-specific effects.
Methods: Genome-wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimer's Disease Genetics Consortium.