Publications by authors named "Naj A"

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.

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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.

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Article Synopsis
  • A study was conducted to investigate the X-chromosome's role in Alzheimer's Disease (AD), which had been overlooked in previous genome-wide association studies.
  • The research included 115,841 AD cases and 613,671 controls, considering different X-chromosome inactivation (XCI) states in females.
  • While no strong genetic risk factors for AD were found on the X-chromosome, seven significant loci were identified, suggesting areas for future research.
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  • Alzheimer's disease (AD) is a common hereditary disorder affecting the elderly, and this study explored its genetic associations using whole genome sequencing data from 13,371 individuals of various ancestries.
  • The researchers found significant genetic variants related to AD, including those at APOE, BIN1, and a specific haplotype on chromosome 14 (PSEN1) in Hispanic populations, alongside variants in LINC00320 in Black individuals.
  • The study highlights the importance of both pooled and subgroup-specific analyses in understanding the complex genetic architecture of AD, revealing rare non-coding variants in the promoter of TOMM40 unrelated to APOE.
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NIAGADS 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.

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Progressive 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.

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Article Synopsis
  • Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease linked to abnormal tau protein accumulation, and previous studies were limited in exploring rare genetic variants due to the use of genotype arrays.* -
  • In this study, whole genome sequencing (WGS) on a large cohort allowed researchers to confirm known genetic loci related to PSP and discover new associations, particularly highlighting a different role for the APOE ε2 allele compared to Alzheimer's disease.* -
  • The findings expand knowledge of PSP's genetic underpinnings and identify potential targets for future research into the disease's mechanisms and treatments.*
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Alzheimer 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).

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Rich 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.

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Introduction: 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).

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  • The study emphasizes the importance of including the X chromosome in Alzheimer’s disease research, underlining its role in sex differences in disease risk.
  • Researchers modeled gene expression in X chromosome genes through advanced statistical methods, using a combination of blood and brain tissue samples.
  • They identified the gene ARMCX6, particularly in females, as a potential risk factor for Alzheimer’s disease, highlighting its relevance in future genetic studies.
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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.

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The 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.

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Article Synopsis
  • Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease linked to tau protein accumulation, and previous studies using genotype arrays overlooked important genetic variations like rare variants and structural changes.* -
  • This study utilized whole genome sequencing (WGS) involving 1,718 PSP patients and 2,944 controls, confirming known genetic markers and discovering new associations, including the unique role of the ε2 allele as a risk factor.* -
  • The findings from this research advance the understanding of PSP genetics, highlighting potential new targets for disease mechanisms and treatment strategies.*
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Introduction: 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.

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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).

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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).

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Article Synopsis
  • - The study addresses the issue of limited ancestral diversity in genome-wide association studies (GWAS), which makes it hard to find genetic risk variants in non-European ancestry groups, focusing on Alzheimer's Disease (AD).
  • - Researchers analyzed a multi-ancestry GWAS dataset within the Alzheimer's Disease Genetics Consortium (ADGC) involving individuals from various ancestries, identifying 13 shared risk loci and 3 ancestry-specific loci, highlighting the benefits of diverse samples.
  • - The findings underscore the importance of including underrepresented populations in genetic research, suggesting that even smaller sample sizes can lead to the discovery of novel genetic variants related to AD and implicating specific biological pathways like amyloid regulation and neuronal development.
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Article Synopsis
  • The study investigates how sex and race influence the relationship between apolipoprotein E (APOE) alleles (ε4 and ε2) and cognitive function in Alzheimer’s disease (AD) across different populations.
  • Using data from four cohorts of older adults (60+ years) who self-identified as either non-Hispanic White or non-Hispanic Black, researchers analyzed cognitive outcomes related to memory and executive function.
  • Findings suggest significant differences in how APOE ε4 impacts cognitive scores based on sex, with the interactions varying by race, indicating that genetic factors influencing cognition in AD are complex and multifaceted.
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Background: 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.

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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).

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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.

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