Association of HLA-DR/DQ Polymorphism With Alzheimer’s Disease

Mansouri, Leila; Klai, Sarra; Gritli, Nasreddine; Fekih-Mrissa, Najiba; Messalmani, Mariem; Bedoui, Ines; Derbali, Hajer; Mrissa, Ridha

doi:10.1097/maj.0000000000000416

Cited by 24 publications

(9 citation statements)

References 33 publications

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“…Given that only B*07 : 02 , DRB1*15 : 01 , DQA1*01 : 02 , and DQB1*06 : 02 showed significant locus-level associations with AD, our findings are consistent with an ambiguous role of HLA-A*02 in AD. In terms of class II alleles, one study by Mansouri and colleagues demonstrated a link between DRB1*15 : 01~DQB1*06 : 02 and AD in a small cohort of Tunisians [62], consistent with our findings. Previous GWASs have found that AD risk is associated with a SNP in DRB5 [63].…”

Section: Discussionsupporting

confidence: 92%

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

et al. 2017

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BackgroundAlzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations.Methods and findingsBuilding on prior work linking the HLA to AD, we used a robust imputation method on two separate case–control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999–2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer’s Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984–2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005–2007 and longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10−4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08–1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A*03:01~B*07:02 (p = 0.03, OR = 1.11 [1.01–1.23]) and class II haplotype DRB1*15:01- DQA1*01:02- DQB1*06:02 (DR15) (p = 0.03, OR = 1.08 [1.01–1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A*03:01~B*07:02 was associated with higher CSF amyloid levels (p = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer’s Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, β ± standard error = −0.2 ± 0.06]). In a subset of the same cohort, dose of DR15 was also asso...

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Section: Discussionsupporting

confidence: 92%

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

et al. 2017

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“…Interestingly, as shown in Tables 1 and 2, many of the genes with substantial power gains by TWAS‐LQ and MV‐TWAS over that of the standard UV‐TWAS are related to AD as discussed in the literature. For example, the genes in the human leukocyte antigen (HLA) complex have been considered risk factors of late‐onsite AD (Mansouri et al, 2015; Steele et al, 2017; Wang et al, 2020). APOC1 is another widely known gene, related to APOE , that affects the risk of AD (Q. Zhou & Zhao, 2014; X. Zhou et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Statistical power of transcriptome‐wide association studies

Xue

Pan

2022

Genetic Epidemiology

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Transcriptome-Wide Association Studies (TWASs) have become increasingly popular in identifying genes (or other endophenotypes or exposures) associated with complex traits. In TWAS, one first builds a predictive model for gene expressions using an expression quantitative trait loci (eQTL) data set in stage 1, then tests the association between the predicted gene expression and a trait based on a large, independent genome-wide association study (GWAS) data set in stage 2. However, since the sample size of the eQTL data set is usually small and the coefficient of multiple determination (i.e., R 2 ) of the model for many genes is also small, a question of interest is to what extent these factors affect the statistical power of TWAS. In addition, in contrast to a standard (univariate) TWAS (UV-TWAS) considering only a single gene at a time, multivariate TWAS (MV-TWAS) methods have recently emerged to account for the effects of multiple genes, or a gene's nonlinear effects, simultaneously. With the absence of the power analysis for these MV-TWAS methods, it would be of interest to investigate whether one can gain or lose power by using the newly proposed MV-TWAS instead of UV-TWAS. In this paper, we first outline a general method for sample size/power calculations for two-sample TWAS, then use real data-the Alzheimer's Disease Neuroimaging Initiative (ADNI) expression quantitative trait loci (eQTL) data and the Genotype-Tissue Expression (GTEx) eQTL data for stage 1, the International Genomics of Alzheimer's Project Alzheimer's disease (AD) GWAS summary data and UK Biobank (UKB) individual-level data for stage 2-to empirically address these questions. Our most important conclusions are the following. First, a sample size of a few thousands (~8000) would suffice in stage 1, where the power of TWAS would be more determined by cis-heritability of gene expression. Second, as in the general

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“…The HLA region has proven of interest in AD, particularly the HLA Class II region [18,[24][25][26] with evidence for the HLA Class I regions as well [27,28]. Five independent HLA genetic regions were identified as having study wide significance in at least one endophenotype, with additional HLA Class I related markers in KIR3DL1 and KIR2DL4.…”

Section: Discussionmentioning

confidence: 99%

Genome Wide Analysis Across Alzheimer’s Disease Endophenotypes: Main Effects and Stage Specific Interactions

Jacobson

Nho

Risacher

et al. 2021

Preprint

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Introduction: Genetic association analysis of key Alzheimer's disease (AD) endophenotypes may provide insight into molecular mechanisms and genetic contributions. Methods: Major AD endophenotypes based on the A/T/N (Amyloid-beta, Tau, and Neurodegeneration) biomarkers and cognitive performance were selected from Alzheimer's Disease Neuroimaging Initiative (ADNI) in up to 1,565 subjects. Genome-wide association analysis of quantitative phenotypes was performed using a main SNP effect and a SNP by Diagnosis interaction (SNPxDX) model to identify stage specific genetic effects. Results: Sixteen novel or replicated loci were identified in the main effect model, with six (SRSF10, MAPT, XKR3, KIAA1671, ZNF826P, and LOC100507506) meeting study significance thresholds with the A/T/N biomarkers. The SNPxDX model identified three study significant genetic loci (BACH2, EP300, PACRG-AS1) associated with a neuroprotective effect in later AD stage endophenotypes. Discussion: An endophenotype approach identified novel genetic associations and new insights into the associations that may otherwise be missed using conventional case-control models.

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Association of HLA-DR/DQ Polymorphism With Alzheimer’s Disease

Cited by 24 publications

References 33 publications

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

Statistical power of transcriptome‐wide association studies

Genome Wide Analysis Across Alzheimer’s Disease Endophenotypes: Main Effects and Stage Specific Interactions

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