CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking

Weng, Pei-Hsuan; Chen, Jen‐Hau; Chen, Ta‐Fu; Sun, Yu; Wen, Li-Li; Yip, Ping-Keung; Chu, Yi-Min; Chen, Yen‐Ching

doi:10.1038/srep27231

Cited by 21 publications

(13 citation statements)

References 54 publications

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“…Here, the authors report that smoking increased the risk of dementia by an OR= 2.18 compared to non-smokers, which was not modified by APOE genotype (Tyas et al, 2003). In another study, the rs7179008 polymorphism of CHRNA7 (α7 nicotinic acetylcholine receptor) decreased risk in LOAD (AOR=0.29) and protect against increased risk of smoking in LOAD (Weng et al, 2016).…”

Section: Gene Environment Interactionsmentioning

confidence: 75%

Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine

Eid

Mhatre

Richardson

2019

Pharmacology & Therapeutics

112

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Alzheimer's disease (AD) is the leading cause of dementia in the United States and afflicts greater than 5.7 million Americans in 2018. Therapeutic options remain extremely limited to those that are symptom targeting, while no drugs have been approved for the modification or reversal of the disease itself. Risk factors for AD including aging, the female sex, as well as carrying an APOE4 genotype. These risk factors have been extensively examined in the literature, while less attention has been paid to modifiable risk factors, including lifestyle, and environmental risk factors such as exposures to air pollution and pesticides. This review highlights the most recent data on risk factors in AD and identifies gene by environment interactions that have been investigated. It also provides a suggested framework for a personalized therapeutic approach to AD, by combining genetic, environmental and lifestyle risk factors. Understanding modifiable risk factors and their interaction with non-modifiable factors (age, susceptibility alleles, and sex) is paramount for designing personalized therapeutic interventions.

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Section: Gene Environment Interactionsmentioning

confidence: 75%

Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine

Eid

Mhatre

Richardson

2019

Pharmacology & Therapeutics

112

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“…Previous studies of gene-environment interactions in AD have focused on candidate genes, stemming from prior AD or vascular disease GWASs (e.g. [31, 32]). We focused on a genome-wide, unbiased interaction approach to identify novel genes that interact with CVRFs to increase susceptibility to AD.…”

Section: Discussionmentioning

confidence: 99%

FMNL2 interacts with cerebrovascular risk factors to alter Alzheimer’s disease risk

Raghavan

Sariya

Lee

et al. 2020

Preprint

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INTRODUCTION: Late-onset Alzheimer's disease (AD) frequently co-occurs with cerebrovascular disease. We hypothesized that interactions between genes and cerebrovascular risk factors (CVRFs) contribute to AD risk. METHODS: Participants age 65 years or older from five multi-ethnic cohorts (N=14,669) were included in genome-wide association meta-analyses for AD including an interaction factor for a CVRF score created from body mass index, hypertension, heart disease, and diabetes. Significant gene level results were substantiated using neuropathological and gene expression data. RESULTS: At the gene-level, FMNL2 interacted with the CVRF score to significantly modify AD risk (p= 7.7x10-7). A SNP within FRMD4B, rs1498837, was nominally significant (p=7.95x10-7). Increased FMNL2 expression was significantly associated with brain infarcts and AD. DISCUSSION: FMNL2 is highly expressed in the brain and has been associated with ischemic stroke and failures in endosomal trafficking, a major pathway in AD pathology. The results highlight an interaction between FMNL2 and CVRFs on AD susceptibility.

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“…Products of CHRNA7 and CACNA1H are neurotransmitters and voltage channels responsible for the influx of Ca 2+ . These are involved in the regulation of the downstream cascade of reactions in the cellular pathways [50,51]. CHRNA7 microduplication has been detected in a subject with autism and moderate cognitive impairment [46].…”

Section: Discussionmentioning

confidence: 99%

Identification of primary copy number variations reveal enrichment of Calcium, and MAPK pathways sensitizing secondary sites for autism

Agarwala

Veerappa

Ramachandra

2020

Egypt J Med Hum Genet

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Background Autism is a neurodevelopmental condition with genetic heterogeneity. It is characterized by difficulties in reciprocal social interactions with strong repetitive behaviors and stereotyped interests. Copy number variations (CNVs) are genomic structural variations altering the genomic structure either by duplication or deletion. De novo or inherited CNVs are found in 5–10% of autistic subjects with a size range of few kilobases to several megabases. CNVs predispose humans to various diseases by altering gene regulation, generation of chimeric genes, and disruption of the coding region or through position effect. Although, CNVs are not the initiating event in pathogenesis; additional preceding mutations might be essential for disease manifestation. The present study is aimed to identify the primary CNVs responsible for autism susceptibility in healthy cohorts to sensitize secondary-hits. In the current investigation, primary-hit autism gene CNVs are characterized in 1715 healthy cohorts of varying ethnicities across 12 populations using Affymetrix high-resolution array study. Thirty-eight individuals from twelve families residing in Karnataka, India, with the age group of 13–73 years are included for the comparative CNV analysis. The findings are validated against global 179 autism whole-exome sequence datasets derived from Simons Simplex Collection. These datasets are deposited at the Simons Foundation Autism Research Initiative (SFARI) database. Results The study revealed that 34.8% of the subjects carried 2% primary-hit CNV burden with 73 singleton-autism genes in different clusters. Of these, three conserved CNV breakpoints were identified with ARHGAP11B, DUSP22, and CHRNA7 as the target genes across 12 populations. Enrichment analysis of the population-specific autism genes revealed two signaling pathways—calcium and mitogen-activated protein kinases (MAPK) in the CNV identified regions. These impaired pathways affected the downstream cascades of neuronal function and physiology, leading to autism behavior. The pathway analysis of enriched genes unravelled complex protein interaction networks, which sensitized secondary sites for autism. Further, the identification of miRNA targets associated with autism gene CNVs added severity to the condition. Conclusion These findings contribute to an atlas of primary-hit genes to detect autism susceptibility in healthy cohorts, indicating their impact on secondary sites for manifestation.

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CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking

Cited by 21 publications

References 54 publications

Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine

Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine

FMNL2 interacts with cerebrovascular risk factors to alter Alzheimer’s disease risk

Identification of primary copy number variations reveal enrichment of Calcium, and MAPK pathways sensitizing secondary sites for autism

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