DNMBP is genetically associated with Alzheimer dementia in the Belgian population

Genetic association of the dynamin binding protein gene (DNMBP) on chromosome 10 with late-onset Alzheimer's disease (AD) was reported among Japanese. Here, we assessed the genetic role of DNMBP in an extended Belgian AD group using a gene-wide association approach. A total of 18 SNPs across the DNMBP locus were genotyped in 555 late-onset AD patients and 638 healthy control individuals. Significant associations were observed for two SNPs (rs3740057 and rs10883421). Haplotype analysis identified association with haplotype blocks in the 3’ region of DNMBP comprising rs2862919, rs11190302, rs10509739, rs2256700 and comprising rs3740057 and rs6584331. Stratification for APOE 4 status showed that association was only present in the APOE 4 negative subgroup. Sliding-window analyses provided further evidence for association with the 3’–end of DNMBP both for the total and for the APOE 4 negative group. Taken together our findings underscore a role for DNMBP in the genetic risk for late-onset AD in the Belgian population.     

Interaction between the APOE epsilon4 allele and the APH-1b c + 651T > G SNP in Alzheimer's disease

The γ-secretase complex is a multimeric aspartyl protease which plays a pivotal role in the production of amyloid β-peptide, the main component of senile plaques in Alzheimer's disease (AD). APH-1a and APH-1b have been recently identified as important subunits of the γ-secretase complex. We previously studied sequence variations in both genes and their association with AD in a small Italian population. The rare polymorphism c + 651T > G in APH-1b showed a possible interaction with the Apolipoprotein E (APOE) 4 allele in the AD population sample. We extended our genetic analysis to 449 AD patients and 435 controls and, in AD cases, we found a significant interaction (P = 0.001) between the allelic variants in the two genes, resulting in a marked increase of the relative risk for AD (OR = 28.6). Despite the amino acid substitution does not seem to modify either the intracellular localization or the half-life of APH-1b protein, these data suggest that a cooperative mechanism involving APOE and APH-1b plays a role in the susceptibility to develop AD.     

Alpha-2-macroglobulin gene, oxidized low-density lipoprotein receptor-1 locus, and sporadic Alzheimer's disease

A total sample of 169 AD patients, and 264 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotypized for alpha-2-macroglobulin (A2M) Val1000/Ile single-nucleotide polymorphism (SNP) (rs669), apolipoprotein E (APOE), and SNPs (+1073 and +1071) in the oxidized low-density lipoprotein receptor-1 (OLR1) gene on chromosome 12. A2M allele and genotype frequencies were similar between AD patients and controls, also after stratification for late onset (≥70 years) and early onset (<70 years) or APOE 4 status. However, there was evidence in support of LD between the OLR1 + 1071, the OLR1 + 1073, and the rs669 SNPs, with T-C-A haplotype being associated with significant increased risk of AD in both the whole sample and when we stratified according to early and late onset AD subjects, with the allelic association with AD predominantly from the OLR1 + 1073 SNP, further supporting the role of OLR1 as a candidate risk gene for sporadic AD.     

Cultured peripheral blood mast cells from chronic idiopathic urticaria patients spontaneously degranulate upon IgE sensitization: Relationship to expression of Syk and SHIP-2

Recently, signaling changes in the FcRI pathway involving inositol lipid phosphatases have been identified in the basophils of chronic idiopathic urticaria (CIU) subjects. Based on the profile of basophil FcRI-mediated histamine degranulation, we have segregated CIU subjects into two groups, CIU Responder (CIU R) or CIU Nonresponder (CIU NR). In the present study, we compared expression of SHIP-1, SHIP-2, and Syk protein to histamine release (HR) from mast cells (MC) cultured from the peripheral blood of CIU R, CIU NR, and normal subjects. The MC of CIU R donors contained significantly increased Syk and decreased SHIP-2 as compared to CIU NR (Syk: p = 0.038, SHIP-2: p = 0.038) and normals (Syk: p = 0.042, SHIP-2: p = 0.027). Spontaneous HR from CIU donors was increased two-fold compared to normals (p = 0.04). In summary, our results suggest a possible predilection for urticarial MC to spontaneously degranulate upon IgE sensitization contributing to the increased pruritis associated with CIU.     

Association of Existing and New Candidate Genes for Anxiety,Depression and Personality Traits in Older People

Genetic variants that have previously been associated with personality traits and/or psychological distress, or inflammatory marker levels were investigated for their relationship to self-rated personality traits, anxiety, and depression in two elderly Scottish cohorts. Ten genes (29 SNPs) were investigated in the Lothian Birth Cohort 1936 (~70 years, N = 1,091). Four of these genes and seven others (35 SNPs) were tested in the Lothian Birth Cohort 1921 who were measured on the same traits and states on two occasions (~80 years, N = 550; 87 years, N = 229). For previously investigated candidate genes, some support (at a nominal significance level of 0.05/0.01) was found for association between NOS1 and personality traits (especially extraversion), PSEN1 and depression/neuroticism, and GRIK3 and depression. Of the inflammatory marker candidate genes, TF showed some association with psychological distress. No SNPs withstood the correction to significance level for multiple testing. Nevertheless, the results will be of importance to future meta-analyses of these candidate genes in relation to psychological distress and personality.     

A SNP in the ACT gene associated with astrocytosis and rapid cognitive decline in AD

There is biochemical and animal model evidence supporting a pathological role of the ACT gene in AD. However, direct genetic evidence remains controversial and has been mostly limited to individual single nucleotide polymorphism (SNP) analysis. To resolve this apparent conflict we have used a high-density ACT SNP map, constructed haplotypes and explored correlations with phenotype. SNPs were identified by sequencing and used to construct haplotypes in 668 AD patients and 419 controls and a case–control association study was performed. Five SNPs, comprising five common haplotypes, represented 93% of ACT gene variation. Although no single SNP or haplotype was associated with AD status, a SNP in intron 2 was associated with later onset and more rapid cognitive decline (P = 0.04). This SNP was both individually associated with severe astrocytosis (P = 0.004) in AD patients and when combined with the signal sequence SNP (P = 0.002). This suggests that astrocytosis may have a protective function for a limited period in some patients. These SNP associations either support a direct role for the ACT gene, in AD pathology or alternatively reflect linkage with polymorphisms in other genes nearby.     

Associations between sleep duration and cognitive impairment in mild cognitive impairment

The prevalence of mild cognitive impairment (MCI) increases among elderly people and is associated with a high risk of dementia. Identifying factors that may contribute to the progress of MCI to dementia is critical. The objective of this study was to examine the association of objective sleep with cognitive performance in MCI patients. A subsample of 271 participants with a diagnosis of probable Alzheimer's disease (AD; N = 50) or mild cognitive impairment (MCI; N = 121) and 100 persons who were not cognitively impaired (NI) were recruited from a large population‐based cohort in the island of Crete, Greece (3140 older adults aged >60 years). All participants underwent extensive neuropsychiatric/neuropsychological evaluation and a 3‐day 24‐hr actigraphy. Objective sleep variables and their association with neuropsychological performance were examined across the three groups, controlling for demographics, body mass index, depression, sleep apnea symptoms and psychotropic medications. Patients with AD had significantly longer 24‐hr total sleep time (TST) compared to the MCI and NI groups. Long 24‐hr TST was associated with reduced performance on tasks that placed significant demands on attention and processing speed in the MCI group and the AD group. Elderly patients with MCI have similar objective sleep duration to normal controls, whereas AD patients sleep longer. Long sleep duration in patients with multidomain subtypes of MCI is associated with critical non‐memory cognitive domains. It appears that within the MCI group those that sleep longer have more severe cognitive impairment.     

No Association Between Cholinergic Muscarinic Receptor 2 (CHRM2) Genetic Variation and Cognitive Abilities in Three Independent Samples

Cognitive ability has a substantial genetic component and more than 15 candidate genes have been identified over the past 8 years. One gene that has been associated with general cognitive ability is the cholinergic muscarinic 2 receptor (CHRM2). In an attempt to replicate this finding we typed marker rs8191992 (the originally reported CHRM2 SNP) in two population based cohorts—one Scottish aged over 50 years (N = 2,091) and the other English comprising non-demented elderly participants (N = 758)—and a family-based Australian adolescent sample (N = 1,537). An additional 29 SNPs in CHRM2 were typed in the Australian sample and a further seven in the English cohort. No significant association was found between CHRM2 and diverse measures of cognitive ability in any of the samples. In conclusion, this study does not support a role for CHRM2 in cognitive ability. The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. Edited by Chandra A. Reynolds.     

Polymorphisms in Dopamine Transporter (<Emphasis Type="Italic">SLC6A3</Emphasis>) are Associated with Stimulant Effects of <Emphasis Type="Italic">d</Emphasis>-Amphetamine: An Exploratory Pharmacogenetic Study Using Healthy Volunteers

Individuals vary in their subjective responses to stimulant drugs, and these differences are believed to be partially genetic in origin. We evaluated associations between mood, cognitive and cardiovascular responses to d-amphetamine and four polymorphisms in the dopamine transporter (SLC6A3): rs460000, rs3756450, rs37022 and rs6869645. Healthy Caucasian male and female volunteers (N = 152) participated in a double-blind, crossover design study in which they received placebo, 10 and 20 mg of d-amphetamine. We measured self-reported rating of mood, performance on the Digit Symbol Substitution Task, blood pressure and heart rate. Individuals with the C/C genotype at rs460000 (N = 83) reported approximately twofold higher ratings of stimulation and euphoria relative to the A/A+A/C (N = 69) genotype group, at both the 10 and 20 mg doses. No other responses or SNPs showed significant effects. rs460000 is in perfect LD with rs463379 (CEU: D′ = 1; r ² = 1), which was not studied here, but has been associated with etiology of Attention Deficit Hyperactivity Disorder (ADHD). These findings suggest a pleiotropic effect of this polymorphic locus on both ADHD and sensitivity to the subjective effects of amphetamine.     

Single nucleotide polymorphisms within MicroRNAs,MicroRNA targets,and MicroRNA biogenesis genes and their impact on colorectal cancer survival

We have shown that single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes, miRNA target genes, and miRNA biogenesis genes minimally contribute to colon cancer risk. It is possible that these SNPs alter survival. We analyzed 565 SNPs in or adjacent to microRNAs, target genes, or biogenesis genes, using 1,115 cases and 1,173 controls; 837 cases had survival information. We tested SNPs for associations with colorectal cancer (CRC) survival using a Cox proportional hazard model adjusting for age, study center, gender, AJCC disease stage, and MSI tumor status. Multiple comparison adjustments were made using the step‐down Bonferroni correction. SNPs associated with survival (P_raw < 0.05) also were assessed with messenger RNA (mRNA). Seven of the 565 SNPs analyzed were associated significantly with CRC survival after adjustment for multiple comparisons. Six of these increased risk of dying, and one, rs12140 (ADAMTS1) decreased risk of dying from CRC (HRR = 0.44, 95% CI (0.24, 0.83; P_Holm = 0.011). Six SNPs altered colon cancer risk and five were associated with altered mRNA expression across genotypes. One SNP, rs2059691 (PRKRA), was associated with increased mRNA expression and worse survival, and one SNP, rs6598964 (LIN28A), decreased risk of developing colon cancer [OR = 0.77 95% CI (0.61, 0.98)] and increased risk of dying from CRC (HRR = 2.26 95% CI (1.52, 3.36). P_Holm = 0.003). The few SNPs associated with CRC survival, colon cancer risk, or with mRNA expression, resided in genes that influence metastasis and angiogenesis. © 2017 Wiley Periodicals, Inc.     

Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene and the rate of cognitive decline in Alzheimer's disease

The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the regulatory regions of the apolipoprotein E (APOE) gene modify the well-established epsilon4-associated risk for Alzheimer's disease (AD). Sequencing of the APOE gene regulatory regions revealed four previously reported promoter SNPs and one novel SNP in the previously described macrophage enhancer (ME.1). In addition, we also studied the two classic allelic missense SNPs that define epsilon2/epsilon3/epsilon4 status in a case-control association study. Analysis of pair-wise linkage disequilibrium (LD) of the five regulatory region SNPs with classic APOE SNPs revealed a previously unreported 7 kb LD block covering the entire APOE gene, part of the promoter and 3' enhancer region. We report here that in a case-control association study (N=719) of the seven SNPs, the genotype at codon 112 captures all the information required to assess disease risk. To explore correlations with quantitative traits, 169 patients were studied in whom rates of cognitive decline were available. In addition to the epsilon4 allele, two regulatory region SNPs were associated with the rate of cognitive decline in AD patients. This study highlights the effect of APOE gene variation on risk of AD and rate of cognitive decline and demonstrates that a single SNP, which confers epsilon4 status, captures all of the risk of developing AD but two SNPs in the regulatory region may affect the rate of cognitive decline in AD patients.     

Association Between Polymorphisms of the Dopamine Receptor D2 and Catechol-o-Methyl Transferase Genes and Cognitive Function

The dopaminergic neurotransmitter system of the brain is involved in working memory and other cognitive functions. Studies suggest an important role for dopamine synthesis and uptake in modulation of human cognitive processes. We studied the association between polymorphisms in the catechol-o-methyl transferase (COMT) and dopamine receptor D2 (DRD2) genes and general cognitive ability in a secondary analysis of 2091 men and women, aged 55–80 years living in Scotland. General cognitive ability ‘g’ was derived from five cognitive tests of different domains. COMT was not associated with cognitive ability in this population. The DRD2 C:C genotype of rs6277 was associated with decreased general cognitive ability ‘g’ (p = 0.003), and DRD2 rs1800497 heterozygotes had lowest mean general cognitive ability ‘g’ (p = 0.007). There was an indication of a potential interaction between the DRD2 SNPs.     

SPINK5 is associated with early‐onset and CHI3L1 with late‐onset atopic dermatitis

We have recently showed that filaggrin (FLG) mutations are associated only with early‐onset of AD, but not with late‐onset of AD. Consequently, other susceptibility genes should receive attention, especially in patients with late‐onset of AD. Our aim was to assess the associations between development of AD and the polymorphisms rs2303067 in SPINK5 and rs490928 in CHI3L1. A study population of 241 AD patients and 164 healthy controls was genotyped for two polymorphisms (rs2303067 in SPINK5 and rs490928 in CHI3L1). Rs2303067 in SPINK5 was significantly associated with early‐onset AD (≤8 years: p = .003; OR = 2.57) and was characterized by the need for hospitalization (p = .006; OR = 2.76), prolonged duration (≥10 years; p = .008; OR = 2.32) and more body parts affected (p = .015; OR = 2.01). In contrast, rs490928 in CHI3L1 was associated with late‐onset AD (>8 years: p = .048; OR = 1.65) and was characterized by no need for hospitalization (p = .049; OR = 1.59), shorter duration (<10 years; p = .017; OR = 1.94) and fewer body parts affected (p = .049; OR = 1.75). Our results confirmed that different AD phenotypes, specifically early‐ and late‐onset AD, have different genetic backgrounds. Early‐onset AD was associated with rs2303067 in SPINK5, which is involved in skin barrier functioning, and late‐onset was associated with rs4950928 in CHI3L1, which is involved in the immune response. Future studies should examine the early‐ versus late‐onset subgrouping more closely.     

Differential involvement of μ1-opioid receptors in endomorphin- and β-endorphin-induced G-protein activation in the mouse pons/medulla

Several genetic mouse models of differential sensitivity to opioids have been used to investigate the mechanisms underlying individual variation in responses to opioids. The CXBK mice are inbred recombinant mice which have a lower level of μ₁-opioid receptors than their parental strain. Endomorphin-1 and endomorphin-2 are endogenous opioid peptides that are highly selective for μ-opioid receptors, while β-endorphin, which is also an endogenous opioid peptide, is non-selective for μ-, δ- and putative -opioid receptors. The present study was designed to investigate the effects of these endogenous opioid peptides on G-protein activation by monitoring guanosine-5′-o-(3-[³⁵S]thio)triphosphate binding to pons/medulla membranes of CXBK mice and their parental strain C57BL/6ByJ mice. Endomorphin-1 (0.1–10 μM), endomorphin-2 (0.1–10 μM) and β-endorphin (0.1–10 μM) increased guanosine-5′-o-(3-[³⁵S]thio)triphosphate binding to the pons/medulla membranes from C57BL/6ByJ and CXBK mice in a concentration-dependent manner. However, the increases of guanosine-5′-o-(3-[³⁵S]thio)triphosphate binding induced by either endomorphin-1 or endomorphin-2 in CXBK mice were significantly much lower than those in C57BL/6ByJ mice. However, no significant difference was found in the increases of the guanosine-5′-o-(3-[³⁵S]thio)triphosphate binding induced by β-endorphin in C57BL/6ByJ and CXBK mice. Moreover, whereas the increase of guanosine-5′-o-(3-[³⁵S]thio)triphosphate binding induced by 10 μM endomorphin-1 or endomorphin-2 were almost completely blocked by a μ-opioid receptor antagonist β-funaltrexamine (10 μM) in both strains, the increase of guanosine-5′-o-(3-[³⁵S]thio)triphosphate binding induced by 10 μM β-endorphin was attenuated to approximately 70% of stimulation by co-incubation with 10 μM β-funaltrexamine in both strains. The residual stimulation of [³⁵S]guanosine-5′-o-(3-thio)triphosphate binding by 10 μM β-endorphin in the presence of 10 μM β-funaltrexamine was further attenuated by the addition of putative -opioid receptor partial agonist β-endorphin (1–27) (1 μM) in both strains. Like the endomorphins, the synthetic μ-opioid receptor agonist [ -Ala²,N-MePhe⁴,Gly-ol⁵]enkephalin at 10 μM showed lower increases of guanosine-5′-o-(3-[³⁵S]thio)triphosphate binding in CXBK mice than those in C57BL/6ByJ mice. However, there was no strain difference in the stimulation of guanosine-5′-o-(3-[³⁵S]thio)triphosphate binding induced by 10 μM of the selective δ₁-opioid receptor agonist [ -Pen^2,5]enkephalin, δ₂-opioid receptor agonist [ -Ala²]deltorphin II or κ-opioid receptor agonist U50,488H.The results indicate that the G-protein activation by endomorphin-1 and endomorphin-2 in the mouse pons/medulla is mediated by both μ₁- and μ₂-opioid receptors. Moreover, β-endorphin-induced G-protein activation in the mouse pons/medulla is, in part, mediated by μ₂- and putative -, but not by μ₁-opioid receptors.     

A Genome-Wide Association Study of Social and Non-Social Autistic-Like Traits in the General Population Using Pooled DNA, 500 K SNP Microarrays and Both Community and Diagnosed Autism Replication Samples

Two separate genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with social and nonsocial autistic-like traits. We predicted that we would find SNPs associated with social and non-social autistic-like traits and that different SNPs would be associated with social and nonsocial. In Stage 1, each study screened for allele frequency differences in ~430,000 autosomal SNPs using pooled DNA on microarrays in high-scoring versus low-scoring boys from a general population sample (N = ~400/group). In Stage 2, 22 and 20 SNPs in the social and non-social studies, respectively, were tested for QTL association by individually genotyping an independent community sample of 1,400 boys. One SNP (rs11894053) was nominally associated (P < .05, uncorrected for multiple testing) with social autistic-like traits. When the sample was increased by adding females, 2 additional SNPs were nominally significant (P < .05). These 3 SNPs, however, showed no significant association in transmission disequilibrium analyses of diagnosed ASD families.