Gene-based aggregate SNP associations between candidate AD genes and cognitive decline

Nettiksimmons, Jasmine; Tranah, Gregory J.; Evans, Daniel S.; Yokoyama, Jennifer S.; Yaffe, Kristine

doi:10.1007/s11357-016-9885-2

Cited by 58 publications

(53 citation statements)

References 33 publications

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“…Notably, no group differences were observed on common standardized measures of declarative memory (delayed recall of semantic or episodic memories), suggesting that the AG risk genotype is specific to impairing generalization of learning in older adults who are otherwise cognitively healthy on measures of declarative memory. In other studies with nondemented elderly (Andrews, Das, Anstey, & Easteal, ; Andrews, Das, Cherbuin, Anstey, & Easteal, ; Engelman et al, ), as well as, AD patients (Chung et al, ; Nettiksimmons, Tranah, Evans, Yokoyama, & Yaffe, ), ABCA7 risk variants were related to variations in episodic memory using standardized assessments. Our results therefore suggest that the concurrent discrimination and generalization behavioral paradigm may be a useful tool for assessing the mild cognitive deficits seen in the earliest phases of prodromal AD before the more severe and more commonly reported deficits in episodic memory arise later in the course of the disease.…”

Section: Discussionmentioning

confidence: 85%

ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training

et al. 2018

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Using high‐resolution resting state functional magnetic resonance imaging (fMRI), the present study tested the hypothesis that ABCA7 genetic risk differentially affects intra‐medial temporal lobe (MTL) functional connectivity between MTL subfields, versus internetwork connectivity of the MTL with the medial prefrontal cortex (mPFC), in nondemented older African Americans. Although the association of ABCA7 risk variants with Alzheimer's disease (AD) has been confirmed worldwide, its effect size on the relative odds of being diagnosed with AD is significantly higher in African Americans. However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to AD risk conferred by ABCA7. In a case–control fMRI study of 36 healthy African Americans, we observed ABCA7 related impairments in behavioral generalization that was mediated by dissociation in entorhinal cortex (EC) resting state functional connectivity. Specifically, ABCA7 risk variant was associated with EC‐hippocampus hyper‐synchronization and EC‐mPFC hypo‐synchronization. Carriers of the risk genotype also had a significantly smaller anterolateral EC, despite our finding no group differences on standardized neuropsychological tests. Our findings suggest a model where impaired cortical connectivity leads to a more functionally isolated EC at rest, which translates into aberrant EC‐hippocampus hyper‐synchronization resulting in generalization deficits. While we cannot identify the exact mechanism underlying the observed alterations in EC structure and network function, considering the relevance of Aβ in ABCA7 related AD pathogenesis, the results of our study may reflect the synergistic reinforcement between amyloid and tau pathology in the EC, which significantly increases tau‐induced neuronal loss and accelerates synaptic alterations. Finally, our results add to a growing literature suggesting that generalization of learning may be a useful tool for assessing the mild cognitive deficits seen in the earliest phases of prodromal AD, even before the more commonly reported deficits in episodic memory arise.

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Section: Discussionmentioning

confidence: 85%

ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training

et al. 2018

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“…99 The association of this SNP was replicated in a Chinese cohort, 101 and further work showed that this SNP is associated with cis-gene expression levels of DRB1 in the temporal cortex and cerebellum. 102 Nettiksimmons et al 103 showed an association of the DRB5-DRB1 clusters with cognitive decline at the gene-level, and more recently methylation of DRB5 in the brain was associated with pathological AD, with another peak of association in DRA. 104 Yokoyama et al 105 determined that variants associated with autoimmune disease are also associated with AD and found that a SNP close to DRB5 is associated with AD and psoriasis.…”

Section: Hla and Parkinson's Diseasementioning

confidence: 99%

The immunogenetics of neurological disease

2017

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Summary Genes encoding antigen‐presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin‐like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non‐coding variation in immunogenetic loci using high‐throughput high‐resolution next‐generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases.

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“…Following up these findings, we recently showed that higher predicted C4 RNA expression was associated with poorer performance on measures of memory function in both patients with SZ and healthy participants, and with reduced cortical activation during visual task performance in healthy participants. 3 This, along with evidence that other risk-related genes and proteins within the complement system are also associated with variation in both cognition and brain structure in both patients and healthy individuals, [4][5][6][7][8][9][10][11][12] led us to consider whether variation within genes that encode the complement system could, as a whole, influence cognition.…”

Section: Introductionmentioning

confidence: 99%

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

Holland

Cosgrove

Whitton

et al. 2019

Genes Brain and Behavior

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Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune‐relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene‐set with an identified role in “complement” function (excluding C4A), we used MAGMA to test if this gene‐set was enriched for genes associated with human intelligence and SZ risk, using genome‐wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene‐set analysis with a complement gene‐set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene‐based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome‐wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.

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Gene-based aggregate SNP associations between candidate AD genes and cognitive decline

Cited by 58 publications

References 33 publications

ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training

ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training

The immunogenetics of neurological disease

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

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