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Genotype-phenotype correlation of T-cell subtypes reveals senescent and cytotoxic genes in Alzheimer's disease.

ABSTRACT: Recent studies identifying expression quantitative trait loci (eQTLs) in immune cells have uncovered important links between disease risk alleles and gene expression trends in monocytes, T cells and other cell types. However, these studies are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer's disease (AD). We have performed RNA sequencing on four T-cell subsets in genome-wide genotyped and well-characterized AD subjects and age- and sex-matched controls from the Religious Orders Study/Memory and Aging Project. We correlated gene expression data with AD neuropathological traits and with single-nucleotide polymorphisms to detect eQTLs. We identified several significant genes involved in T-cell senescence and cytotoxicity, consistent with T-cell RNA sequencing studies in aged/AD cohorts. We identified unexpected eQTLs previously associated with neuropsychiatric disease traits. Finally, we discovered that pathways related to axon guidance and synaptic function were enriched among trans-eQTLs in coding regions of the genome. Our data strengthen the potential link between T-cell senescence and age-related neurodegenerative disease. In addition, our eQTL data suggest that T-cell phenotypes may influence neuropsychiatric disorders and can be influenced by genes involved in neurodevelopmental processes.

SUBMITTER: Dressman D

PROVIDER: S-EPMC9523563 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Genotype-phenotype correlation of T-cell subtypes reveals senescent and cytotoxic genes in Alzheimer's disease.

Dressman Dallin D Buttrick Thomas T Cimpean Maria M Bennett David D Menon Vilas V Bradshaw Elizabeth M EM Vardarajan Badri B Elyaman Wassim W

Human molecular genetics 20220901 19

Recent studies identifying expression quantitative trait loci (eQTLs) in immune cells have uncovered important links between disease risk alleles and gene expression trends in monocytes, T cells and other cell types. However, these studies are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer's disease (AD). We have performed RNA sequencing on four T-cell subsets in genome-wide genotyped and well-characterized AD subj ...[more]

PMID: 35640154

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Project description:INTRODUCTION: Clinical variability associated with the common 22q11.2 microdeletion is well known, and has led to a broad application of FISH diagnostics with probes for loci TUPLE1 or D22S75 (N25), although, rarely reported atypical deletions associated with the same phenotypic spectrum would not be discovered by these probes. As most types of 22q11.2 deletions occur between low copy repeats within the region (LCR22), we assumed that atypical deletions should be more common than has been reported. To address this question and the possibility of a deletion size related genotype-phenotype correlation, we systematically assessed the frequency of typical and atypical 22q11.2 deletions in a large cohort of patients. METHODS: We used a set of 10 fluorescent in situ hybridisation (FISH) DNA probes, capable of detecting all reported and hypothetical deletions between the LCR22, and analysed 350 patients. Deletion sizes in atypical deletions were established by use of further FISH probes. Frequency of certain atypical deletions was analysed in controls by FISH and quantitative PCR. RESULTS: Patients with conotruncal heart defects (ctCHD) and with typical VCFS phenotype showed the common 3 Mb or nested 1.5 Mb deletions (in 18.5% and 78.6%, respectively), but no atypical deletion, while 5% (3/63) of patients with a mildly suggestive, atypical phenotype showed atypical distal deletions, which were not detected in patients with mental retardation of unknown origin or in healthy controls. DISCUSSION: These statistically significant differences demonstrate that atypical distal 22q11.2 deletions are very uncommon in patients with ctCHDs, while atypical congenital heart defects and mild dysmorphism are recognisable feature of atypical distal deletions. Further phenotype-genotype analysis disclosed association of significant developmental delay with the distal part of the common deletion region, and choanal atresia and atypical CHDs with the adjacent distal deletion region.

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Dataset Information

Genotype-phenotype correlation of T-cell subtypes reveals senescent and cytotoxic genes in Alzheimer's disease.

Publications

Genotype-phenotype correlation of T-cell subtypes reveals senescent and cytotoxic genes in Alzheimer's disease.

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