rs4845378

The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.

2024 · Abbas Jalaiei, Mohammad Reza Asadi, Yousef Daneshmandpour, Maryam Rezazadeh, Soudeh Ghafouri‐Fard

Nicotine dependence (ND) is a worldwide health problem. Numerous genetic studies have demonstrated a significant association of variants in nicotinic acetylcholine receptors (nAChRs) with smoking behaviors. However, most of these studies enrolled only subjects of European or African ancestry. In addition, although an increasing body of evidence implies a causal connection of single-nucleotide polymorphisms (SNPs) and epigenetic regulation of gene expression, few studies of this issue have been reported. In this study, we performed both association and interaction analysis for 67 SNPs in CHRNA3-A5, CHRNA7, CHRNB2, and CHRNB4 with ND in a Chinese Han population (N = 5055). We further analyzed cis-mQTL for the three most significant SNPs and 5580 potential methylation loci within these target gene regions. Our results indicated that the SNPs rs1948 and rs7178270 in CHRNB4 and rs3743075 in CHRNA3 were significantly associated with the Fagerstrom Test for Nicotine Dependence (FTND) score (p = 6.6 × 10−5; p = 2.0 × 10−4, and p = 7.0 × 10−4, respectively). Haplotype-based association analysis revealed that two major haplotypes, T-G and C-A, formed by rs3743075–rs3743074 in CHRNA3, and other two major haplotypes, A-G-C and G-C-C, formed by rs1948–rs7178270–rs17487223 in CHRNB4, were significantly associated with the FTND score (p ≤ 8.0 × 10−4). Further, we found evidence for the presence of significant interaction among variants within CHRNA3/B4/A5, CHRNA4/B2/A5, and CHRNA7 in affecting ND, with corresponding p values of 5.8 × 10−6, 8.0 × 10−5, and 0.012, respectively. Finally, we identified two CpG sites (CpG_2975 and CpG_3007) in CHRNA3 that are significantly associated with three cis-mQTL SNPs (rs1948, rs7178270, rs3743075) in the CHRNA5/A3/B4 cluster (p ≤ 1.9 × 10−6), which formed four significant CpG–SNP pairs in our sample. Together, we revealed at least three novel SNPs in CHRNA3 and CHRNB4 to be significantly associated with the FTND score. Further, we showed that these significant variants contribute to ND via two methylated sites, and we demonstrated significant interaction affecting ND among variants in CHRNA5/A3/B4, CHRNA7, and CHRNA4/B2/A5. In sum, these findings provide robust evidence that SNPs in nAChR genes convey a risk of ND in the Chinese Han population.

2018 · Qiang Liu, Haijun Han, Maiqiu Wang, Yinghao Yao, Wen Li, Keran Jiang, Yunlong Ma, Rongli Fan, Jiali Chen, Kunkai Su, Zhongli Yang, Wenyan Cui, Wenji Yuan, Xianzhong Jiang, Jingjing Li, Thomas J. Payne, Jundong Wang, Ming D. Li

치매는 다양한 인지기능 저하와 행동 증상을 유발하는 신경정신장애이다. 전 세계적으로 인구 고령화가 급속도로 진행되면서 치매 발병의 예측 인자를 밝히는 것에 대한 관심이 급증하고 있다…

2014 · 김민지

Neuroimaging studies in subjects at genetic risk of developing Alzheimer's disease: the role of neuroimaging to reveal the endophenotype

2013 · V Berti

A végrehajtó funkciók, melyek depresszióban jelentősen leromolhatnak, jól mérhetők a Stroop teszt segítségével. Ez a mérőmódszer jól reprodukálható, kvantitatív fenotípusos adatokat szolgáltat a végrehajtó funkciók öröklött összetevőit feltáró kandidáns génvizsgálatokhoz. Ennek ellenére viszonylag kevés közlemény foglalkozik a Stroop tesztben elért teljesítmény genetikai faktoraival, melyeket a jelen összefoglaló tárgyal. Ikervizsgálatok alapján a Stroop teszt örökölhetősége 30-60%-ra becsülhető, azaz a genetikai komponens jelentős. Eddig egyetlen teljes genom asszociáció vizsgálatot végeztek a Stroop tesztben produkált teljesítménnyel kapcsolatban, melyben a többszörös tesztelésre való korrekciót követően nem találtak statisztikailag szignifikáns asszociációt mutató polimorfizmust. Az eddig elvégzett kandidáns génvizsgálatok egyes neurotranszmitter rendszer (dopamin, szerotonin, acetilkolin) polimorfizmusok és az APOE ε4 allél genetikai hatását valószínűsítik. Ugyanakkor meglepő, hogy a trofikus és túlélési faktorok genetikai hatásáról mennyire kevés ismerettel rendelkezünk. Összességében elmondhatjuk, hogy a figyelmi funkciókat jellemző Stroop teszt genetikai hátterének feltárásához további vizsgálatok szükségesek.

2012 · Nánási Tibor, Katonai Enikő Rózsa, Sasvári-Székely Mária és Székely Ann

Alzheimer’s disease (AD) is a complex and heterogeneous disorder with an evident genetic background. So far, mutations in three genes have been implicated in the familial, …

2011 · T Sarajärvi

Genetically, Alzheimer's disease is heterogeneous and complex and in most cases displays no single or simple mode of inheritance. Early-onset familial forms of Alzheimer's disease are caused by rare and highly penetrant mutations in APP, PSEN1 and PSEN2 genes, while predisposition to the much more prevalent late-onset form is determined by common genetic risk factors of reduced penetrance. Although the past three decades of genetics research have implicated a bewildering number of such potential risk factors, only the association between polymorphisms in the APOE gene and Alzheimer's disease risk can be considered established to date. Recently, genome-wide association studies have added over three dozen novel potential Alzheimer's disease susceptibility genes, but independent replication data are still lacking for most. In this chapter, we review the status of Alzheimer's disease genetics findings and discuss the potential pathogenetic mechanisms underlying the most viable candidate genes for late-onset Alzheimer's disease.

2011 · Lars Bertram, Rudolph E. Tanzi

The recent discoveries in genome-wide association studies (GWAS) of novel susceptibility loci (CLU, CR1 and PICALM) for Alzheimer's disease (AD) have elicited considerable interest …

2010 · K Sleegers, JC Lambert, L Bertram, M Cruts…

阿尔茨海默病(ad) 为老年性痴呆, 是由环境因素和遗传因素相互影响而发生的复杂异质性疾病, 随着人口的老龄化, 痴呆患病率呈不断上升趋势.“阿尔茨海默病” 的概念最早由德国精神病和…

2010 · 黄越， 马建芳， 黄山

Alzheimer's disease is a genetically complex disorder, and to date, three genes [those that encode amyloid precursor protein (APP) and the presenilins (PS1 and PS2)] have been found to cause early onset familial AD and one genetic risk factor that encodes apolipoprotein E (APOE) lead to late onset AD. In addition to the mutations in 4 known genes associated with AD, mutations in other genes may be implicated in the pathogenesis of the disease. A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades. The search continues for the discovery of additional genetic influences. Here we provide a review on some main AD candidate genes.

2010 · Y BAI, J JIA

With the advent of technologies that allow simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the ‘Top Results’ list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case–control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with AD.

2010 · T M Feulner, Simon M. Laws, Patricia F. Friedrich, Stefan Wagenpfeil, Sebastian H. R. Wurst, Caterina Riehle, Klaus A. Kuhn, Michael Krawczak, Stefan Schreiber, Susanna Nikolaus, Hans Förstl, Alexander Kurz, Markus J. Riemenschneider

We assessed whether smoking behavior was associated with nine polymorphisms in genes coding for the nicotinic receptor subunits α-4 (rs1044394, rs1044396, rs2236196 and rs2273504), α-5 (rs16969968), β-2 (rs2072661 and rs4845378) and β-3 (rs4953 and rs6474413). We conducted an Internet survey and collected saliva by mail for DNA and cotinine analyses, in Switzerland in 2003. We conducted DNA analyses for 277 participants and cotinine analyses for 141 current daily smokers. Cotinine levels were higher in carriers of the CC genotype of CHRNA4 rs1044396 (371 ng/ml) than in those with the CT or TT genotypes (275 ng/ml, p= 0.049), a difference of 0.53 standard deviation units. However, this difference was not robust to correction for multiple testing using Bonferroni adjustment. These 9 polymorphisms were not otherwise associated with smoking behavior and nicotine dependence. There were possible associations between the temperament trait novelty seeking and CHRNA4 rs1044396, CHRNA5 rs16969968 and CHRNB2 rs4845378, but these associations were not robust to correction for multiple testing. We conclude that the analysis of polymorphisms in genes coding for four nicotinic acetylcholine receptor subunits (CHRNA4, CHRNA5, CHRNB2 and CHRNB3) and several smoking-related phenotypes revealed no statistically significant association.

2009 · JF Etter, JC Hoda, N Perroud, M Munafò, C Buresi, C Duret, E Neidhart, A Malafosse…

For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1st, 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 “top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies.

2009 · J Webster, EM Reiman, VL Zismann…

The research program in epigenetics: the birth of a new paradigm (Vineis) Interactions between nutrition and health (Elmadfa) Epigenetics: Comments from an Ecologist (Schiemer) Interaction of hereditary and epigenetic mechanisms in gene expression (Haslberger) HEREDITARY ASPECTS Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and cancer risk: a review of the published meta-analyses (Boccia) The Role of Biobanks for the Understanding of Gene-Environment Interactions (Zatloukal) Case studies on epigenetic inheritance (Kaati) ENVIRONMENTAL AND TOXICOLOGICAL ASPECTS Genotoxic, non-genotoxic and epigenetic mechanisms in chemical hepatocarcinogenesis: Implications for safety evaluation (Bursch) Carcinogens in foods: occurrence, modes of action and modulation of human risks by genetic factors and food components (Knasmuller) NUTRITIONAL ASPECTS From molecular nutrition to nutritional systems biology (Vergeres) Effects of dietary natural compounds on DNA methylation related to cancer chemoprevention and anticancer epigenetic therapy (Stefanska) Health determinants throughout the life cycle (Rust) CASE STUDIES Viral infections and epigenetic control mechanisms (Klaus Huber) Epigenetic aspects in gynaecology and reproductive medicine (Johannes Huber) Epigenetics and Tumorigenesis (Karlic) Epigenetic approaches in oncology (Mader) Epigenetic Dysregulation in Aging and Cancer (Komninou) The impact of genetic and environmental factors in neurodegeneration: emerging role of epigenetics (Migliore) Epigenetic biomarkers in neurodegenerative disorders (Peterlin) Epigenetic mechanisms in asthma (Miller) WAYS FOR TRANSLATION OF THE CONCEPT Public Health Genomics - Integrating Genomics and Epigenetics into National and European Health Strategies and Policies (Schulte in den Baumen) Taking a first step: epigenetic health and responsibility (Gesche)

2009 · Alexander G. Haslberger, Sabine Cressler

The authors evaluated whether there is an excess of statistically significant results in studies of genetic associations with Alzheimer's disease reflecting either between-study heterogeneity or bias. Among published articles on genetic associations entered into the comprehensive AlzGene database (www.alzgene.org) through January 31, 2007, 1,348 studies included in 175 meta-analyses with 3 or more studies each were analyzed. The number of observed studies (O) with statistically significant results (P = 0.05 threshold) was compared with the expected number (E) under different assumptions for the magnitude of the effect size. In the main analysis, the plausible effect size of each association was the summary effect presented in the respective meta-analysis. Overall, 19 meta-analyses (all with eventually nonsignificant summary effects) had a documented excess of O over E: Typically single studies had significant effects pointing in opposite directions and early summary effects were dissipated over time. Across the whole domain, O was 235 (17.4%), while E was 164.8 (12.2%) (P < 10−6). The excess showed a predilection for meta-analyses with nonsignificant summary effects and between-study heterogeneity. The excess was seen for all levels of statistical significance and also for studies with borderline P values (P = 0.05–0.10). The excess of significant findings may represent significance-chasing biases in a setting of massive testing.

2008 · FK Kavvoura, MB McQueen, MJ Khoury…

Despite the health hazards, cigarette smoking is disproportionately frequent among young women. A significant contribution of genetic factors to smoking phenotypes is well established. Efforts to identify susceptibility genes do not generally take into account possible interaction with environment, life experience and psychological characteristics. We recruited 501 female Israeli students aged 20-30 years, obtained comprehensive background data and details of cigarette smoking and administered a battery of psychological instruments. Smoking initiators (n=242) were divided into subgroups with high (n=127) and low (n=115) levels of nicotine dependence based on their scores on the Fagerstrom Tolerance Questionnaire and genotyped with noninitiators (n=142) for single nucleotide polymorphisms (SNPs) in 11 nicotinic cholinergic receptor genes. We found nominally significant (P<0.05) allelic and genotypic association with smoking initiation of SNP rs2072660 and multilocus haplotypes (P<0.007-0.05) in CHRNB2 and nominal (P<0.05) allelic or genotypic association of SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) with nicotine dependence. Employing logistic regression and controlling for known risk factors, the best-fitting model for smoking initiation encompassed a 5 SNP haplotype in CHRNB2, neuroticism and novelty seeking (P=5.9 x 10(-14), Nagelkerke r(2)=0.30). For severity of nicotine dependence, two SNPs in CHRNA7 (rs1909884 and rs883473), one SNP in CHRNA5 (rs680244) and the interaction of a SNP in CHRNA7 (rs2337980) with neuroticism, were included in the model (P=2.24 x 10(-7), Nagelkerke r(2)=0.40). These findings indicate that background factors, psychological characteristics and genetic variation in nicotinic cholinergic receptors contribute independently or interactively to smoking initiation and to severity of nicotine dependence in young women.

2006 · Lior Greenbaum, Kyra Kanyas, Osnat Karni, Yifat Merbl, Tsviya Olender, Anat Horowitz, A Yakir, Doron Lancet, Edna Ben‐Asher, Bernard Lerer

Dementia is a neurodegenerative disorder that causes cognitive dysfunction and behavioral symptoms. As the aging population in the world increases, the interest in early diagnosis of dementia is becoming a necessity. Genes associated with Dementia can be found through Genome Wide Association Study (GWAS) with a large cohort. Although there are many GWAS studies with the Caucasian population, the studies for Asians, in particular Koreans are not sufficient. I identified several high-risk single nucleotide polymorphisms (SNPs) with dementia in Korean population. This cohort study was designed with residents aged over 65 years and under 85 years in Gwangju city. 434 subjects were divided into the normal control group and the dementia group. I examined 29 SNP genotypes for these subject by Taq-man Assay and Fluidigm using DNA extracted from the blood. I analyzed the correlation of each SNP for dementia by chi-square and logistic regression models using 3 types of genetic model (Additive model, Dominant model, Recessive model) after adjustment of the age, sex, APOE-ε4. Futher...

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