EPHA1
Ephrin type-A receptor 1 precursor (EC 2.7.10.1) (hEpha1) (EPH tyrosine kinase) (EPH tyrosine kinase 1) (Erythropoietin-producing hepatoma receptor) (Tyrosine-protein kinase receptor EPH) [EPH] [EPHT] [EPHT1]
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Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and super-cententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not fully characterized. To address these questions, we performed whole-exome sequencing on 100 individuals of 98-108 years age in search of genes with large effect sizes towards the exceptional aging phenotype. Overall, we were unable to identify a rare protein-altering variant or individual genes with an increased burden of rare variants associated with exceptional longevity. Gene burden analysis revealed three genes of nominal statistical significance associated with extreme aging, including LYST, MDN1, and RBMXL1. Several genes with variants conferring an increased risk for AD and other dementias were identified, including TREM2, EPHA1, ABCA7, PLD3, MAPT, and NOTCH3. Larger centenarian studies will be required to further elucidate the genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.
MeSH Terms
- Age Factors
- Aged, 80 and over
- Alzheimer Disease
- Cohort Studies
- Dementia
- Female
- Humans
- Longevity
- Male
- Risk Factors
- Whole Exome Sequencing
Keywords
- Alzheimer’s disease
- Centenarian
- Dementia
- SKAT
- Whole-exome sequencing
Recent genome wide association studies have identified a number of single nucleotide polymorphisms associated with late onset Alzheimer's disease (LOAD). We examined the associations of 24 LOAD risk loci, individually and collectively as a genetic risk score, with cognitive function. We used data from 1,626 non-demented older Australians of European ancestry who were examined up to four times over 12 years on tests assessing episodic memory, working memory, vocabulary, and information processing speed. Linear mixed models were generated to examine associations between genetic factors and cognitive performance. Twelve SNPs were significantly associated with baseline cognitive performance (ABCA7, MS4A4E, SORL1), linear rate of change (APOE, ABCA7, INPP5D, ZCWPW1, CELF1), or quadratic rate of change (APOE, CLU, EPHA1, HLA-DRB5, INPP5D, FERMT2). In addition, a weighted genetic risk score was associated with linear rate of change in episodic memory and information processing speed. Our results suggest that a minority of AD related SNPs may be associated with non-clinical cognitive decline. Further research is required to verify these results and to examine the effect of preclinical AD in genetic association studies of cognitive decline. The identification of LOAD risk loci associated with non-clinical cognitive performance may help in screening for individuals at greater risk of cognitive decline.
MeSH Terms
- Age of Onset
- Alzheimer Disease
- Australia
- Cognitive Dysfunction
- European Continental Ancestry Group
- Female
- Genetic Association Studies
- Genetic Loci
- Genetic Predisposition to Disease
- Humans
- Linear Models
- Longitudinal Studies
- Male
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
Keywords
- Alzheimer’s disease
- cognitive aging
- genetic epidemiology
- genetic risk scores
- longitudinal studies
- single nucleotide polymorphisms
Genome-wide association studies and meta-analyses implicated that increased risk of developing Alzheimer's diseases (AD) has been associated with the ABCA7, APOE, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB1, HLA-DRB4, INPP5D, MEF2C, MS4A4A, MS4A4E, MS4A6E, NME8, PICALM, PLD3, PTK2B, RIN3, SLC24A4, SORL1, and ZCWPW1 genes. In this study, we assessed whether single nucleotide polymorphisms (SNPs) within these 27 AD-associatedgenes are linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. We also analyzed the interactions between lifestyle and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) scores were performed for all subjects to evaluate cognitive functions. Out of the 588 SNPs tested in this study, only the association between CASS4-rs911159 and cognitive aging persisted significantly (P = 2.2 x 10-5) after Bonferroni correction. Our data also showed a nominal association of cognitive aging with the SNPs in six more key AD-associated genes, including EPHA1-rs10952552, FERMT2-rs4901317, MEF2C-rs9293506, PLD3-rs11672825, RIN3-rs1885747, and SLC24A4-rs67063100 (P = 0.0018~0.0097). Additionally, we found the interactions among CASS4-rs911159, EPHA-rs10952552, FERMT2-rs4901317, MEF2C-rs9293506, or SLC24A4-rs67063100 on cognitive aging (P = 0.004~0.035). Moreover, our analysis suggested the interactions of SLC24A4-rs67063100 or MEF2C-rs9293506 with lifestyle such as alcohol consumption, smoking status, physical activity, or social support on cognitive aging (P = 0.008~0.041). Our study indicates that the AD-associated genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-lifestyle interactions.
MeSH Terms
- Age Factors
- Aged
- Alleles
- Alzheimer Disease
- Cognitive Aging
- Epistasis, Genetic
- Female
- Gene-Environment Interaction
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Life Style
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
- Taiwan
Keywords
- Alzheimer’s diseases
- Gerotarget
- Mini-Mental State Examination
- cognitive aging
- gene-gene and gene-lifestyle interactions
- single nucleotide polymorphisms
Single nucleotide polymorphisms (SNPs) in and near ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, complement receptor 1 (CR1), EPHA1, EXOC3L2, FERMT2, HLA cluster (DRB5-DQA), INPP5D, MEF2C, MS4A cluster (MS4A3-MS4A6E), NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1 have been associated with Alzheimer's disease (AD) in large meta-analyses. We aimed to determine whether established AD-associated genes are associated with longitudinal cognitive decline by examining aggregate variation across these gene regions. In two single-sex cohorts of older, community-dwelling adults, we examined the association between SNPs in previously implicated gene regions and cognitive decline (age-adjusted person-specific cognitive slopes) using a Sequence Kernel Association Test (SKAT). In regions which showed aggregate significance, we examined the univariate association between individual SNPs in the region and cognitive decline. Only two of the original AD-associated SNPs were significantly associated with cognitive decline in our cohorts. We identified significant aggregate-level associations between cognitive decline and the gene regions BIN1, CD33, CELF1, CR1, HLA cluster, and MEF2C in the all-female cohort and significant associations with ABCA7, HLA cluster, MS4A6E, PICALM, PTK2B, SLC24A4, and SORL1 in the all-male cohort. We also identified a block of eight correlated SNPs in CD33 and several blocks of correlated SNPs in CELF1 that were significantly associated with cognitive decline in univariate analysis in the all-female cohort.
MeSH Terms
- Aged
- Aging
- Alzheimer Disease
- Cognition Disorders
- DNA
- Female
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Male
- Polymorphism, Single Nucleotide
Keywords
- Candidate AD genes
- Cognitive decline
- SNP associations