Replication of EPHA1 and CD33 associations with late-onset Alzheimer’s disease: a multi-centre case-control study

A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE e4 dosage.

Associations between Mothers' Experiences with the Troubles in Northern Ireland and Mothers' and Childrens' Psychological Functioning: The Moderating Role of Social Identity.

Relatively little research has examined the relations between growing up in a community with a history of protracted violent political conflict and subsequent generations' well-being. The current article examines relations between mothers' self-report of the impact that the historical political violence in Northern Ireland (known, as the Troubles) has on her and her child's current mental health. These relations are framed within the social identity model of stress, which provides a framework for understanding coping responses within societies that have experienced intergroup conflict. Mother-child dyads (N = 695) living in Belfast completed interviews. Results suggest that the mother-reported impact of the Troubles continue to be associated with mothers' mental health, which, in, turn, is associated with her child's adjustment. The strength of mothers' social identity moderated pathways between the impact of the Troubles and her mental health, consistent with the social identity model of stress. (C) 2010 Wiley Periodicals, Inc.

Self-esteem and self-efficacy: Associations with alcohol consumption in a sample of adolescents in Northern Ireland

Cross-sectional and longitudinal studies have reported equivocal findings regarding the association between self-esteem, self-efficacy and adolescent alcohol use. Data were collected from a sample of 11-16-year olds in Northern Ireland (n = 4088) over two consecutive academic years measuring global self-esteem, academic, social and emotional self-efficacy and alcohol involvement. Results showed a domain-specific association between alcohol involvement and self-efficacy, with more problematic alcohol use associated with higher social self-efficacy but lower emotional and academic self-efficacy. Additionally, regression analyses revealed that all self-concept measures significantly predicted drinking group membership. The results are discussed in terms of reported drinking behaviour, interventions with adolescent groups and general development.

Habitat associations of the red squirrel Sciurus vulgaris and grey squirrel S-carolinensis in Northern Ireland

A survey of red and grey squirrel habitat associations in Northern Ireland was conducted between September 1994 and August 1995. Two hundred and sixty-one sites were visited and a list of habitat characteristics for each site was noted. Multiple discriminant function analysis of the habitat type was employed to group squirrel occurrence, while contingency analysis examined independence of habitat type and squirrel species presence. Habitat associations differed between the two species. One-way ANOVAs of habitat data suggested that sites occupied by red squirrels only were predominantly coniferous, at higher altitude and latitude and much larger in area than sites occupied by grey squirrels only, which were mostly deciduous. When both species were sympatric, sites were more likely to be coniferous and larger in area than sites occupied by either species. Grey squirrels were less frequent than expected in upland plantations and more frequent than expected in parkland and gardens; the opposite was true for red squirrels. The mean distance between sites with only red squirrels and the nearest site with grey squirrels was greater than the mean distance between sites with only grey squirrels and the nearest site with red squirrels. An approach to conserving the red squirrel in view of the continued expansion in the grey squirrel's distribution in Ireland is discussed.

GENOTYPE-PHENOTYPE ASSOCIATIONS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE:To examine associations between recognized genetic susceptibility loci and angiographic subphenotypes of the neovascular variant of age-related macular degeneration (nvAMD).METHODS:Participants (247 nvAMD, 52 early age-related macular degeneration [AMD], and 103 controls) were genotyped (complement factor H and ARMS2/HTRA1). nvAMD participants were assigned to one of two subcategories: mainly classic or mainly occult (based on the proportions of classic and occult choroidal neovascularization). nvAMD and early AMD were reassigned to two groups based on the extent and severity of drusen (retinal pigment epithelium dysfunction or not). Univariate and multivariate analysis were used to examine for associations between participant characteristics and genetic loci after adjusting for age, smoking status, and history of cardiovascular disease.RESULTS:Univariate analysis confirmed the known significant associations between AMD stage and age, hypertension, and a history of cardiovascular disease. Those with retinal pigment epithelium dysfunction (F = 5.46; P = 0.02) or a positive smoking history (F = 3.89; P = 0.05) were more likely to have been classified as having mainly an occult rather than a mainly classic lesion. Multivariate analysis showed that significant associations were noted with the number of ARMS2/HTRA1 risk alleles (P

Differential Associations of Job Control Components With Mortality: A Cohort Study, 1986-2005

Inconsistent evidence of the hypothesized favorable effects of high job control on health may have resulted from a failure to treat job control as a multifactor concept. The authors studied whether the 2 components of job control, decision authority and skill discretion, were differentially associated with cause-specific mortality in 13,510 Finnish forest company employees with no history of severe illness. Surveys on work characteristics were carried out in 1986 and 1996, and the respondents were followed up until the end of 2005 by use of the Statistics Finland National Death Registry. During a mean follow-up of 15.5 years, 981 participants died. In the analyses adjusted for confounders, employees with high and intermediate levels of skill discretion had a lower all-cause mortality risk than those with low skill discretion, with hazard ratios of 0.84 (95% confidence interval (CI): 0.69, 1.02) and 0.81 (95% CI: 0.69, 0.96), respectively. In contrast, high decision authority was associated with elevated risks of all-cause, cardiovascular, and alcohol-related mortality, with hazard ratios of 1.28 (95% CI: 1.06, 1.54), 1.49 (95% CI: 1.11, 2.02), and 2.03 (95% CI: 1.03, 4.00), respectively. The results suggest that job control is not an unequivocal concept in relation to mortality; decision authority and skill discretion show different and to some extent opposite associations.

Prevalence of Adverse Childhood Experiences in a University Population: Associations with Use of Social Services

This paper is part of a series published by the Multiple Adverse Childhood Experiences research group based at QUB. First-year undergraduates took part in an online survey, self-reporting on Adverse Childhood Experiences (ACE) and measures of social service contact. The 10-item ACE questionnaire measures abuse, neglect and household dysfunction (current sample ?????????The study achieved a response rate of 18.6%. (N=765; 552 (72.7%) females and 212 (27.2%) males; 21.8% reporting having been educated at a ‘Protestant’ school, 42% reporting having been educated at a ‘Catholic’ school and 20.4% reporting previous school religious affiliation as ‘other’). Despite obvious non-response bias, ACE scores for this student population are comparable with college-educated populations in the US. Current respondents with previous social service contact are over twenty three times more likely than peers to have experienced multiple adversities. Findings support the hypothesis that social service contact, alone, acts as a proxy indicator for the presence of multiple adverse childhood experiences, with no significant elevation in ACE scores for those going through court proceedings or subject to child protection registration. This study supports current concerns by policy makers to target those children experiencing multiple adversities.

Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-Related Macular Degeneration Subtypes

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2×10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3×10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4×10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees

OBJECTIVE The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). METHOD The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs. RESULTS No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10-17, explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families. CONCLUSIONS Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

Genome-wide Association Study Implicates HLA-C*01:02 as a Risk Factor at the Major Histocompatibility Complex Locus in Schizophrenia

BACKGROUND: We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. METHODS: The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. RESULTS: One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 × 10(-9) and in combined samples (rs2523722 p combined = 2.88 × 10(-16)) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. CONCLUSIONS: This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci.

A population-based association study of SNPs of GSTP1, MnSOD, GPX2 and Barrett's esophagus and esophageal adenocarcinoma

Oxidative stress appears to be important in the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Single-nucleotide polymorphisms (SNPs) of antioxidant enzyme genes may play a part in determining individual susceptibility to these diseases. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study is a population-based, case-control study of BE and EAC in Ireland. DNA from EAC (n = 207), BE (> or =3 cm BE at endoscopy with specialized intestinal metaplasia on biopsy, n = 189) and normal population controls (n = 223) were analyzed. Several SNPs spanning the genes for glutathione S-transferase P1 (GSTP1), manganese superoxide dismutase (MnSOD) and glutathione peroxidase 2 (GPX2) were genotyped using multiplex polymerase chain reaction and SNaPshottrade mark. The chi(2) test was used to compare genotype and allele frequencies between case and control subjects. Linkage disequilibrium between SNPs was quantified using Lewontin's D' value and haplotype frequency estimates obtained using Haploview. Eleven SNPs were genotyped (six for GSTP1, three for MnSOD and two for GPX2); all were in Hardy-Weinberg equilibrium. None was significantly associated with EAC or BE even before Bonferroni correction. Odds ratios for EAC for individual SNPs ranged from 0.68 [95% confidence interval (CI) 0.43-1.08] to 1.25 (95% CI 0.73-2.16), and for BE from 0.84 (95% CI 0.52-1.30) to 1.30 (95% CI 0.85-1.97). SNPs in all three genes were in strong linkage disequilibrium (D' > 0.887) but haplotype analysis did not show any significant association with EAC or BE. SNPs involving the GSTP1, MnSOD and GPX2 genes were not associated with BE or EAC. Further studies aimed at identifying susceptibility genes should focus on different antioxidant genes or different pathways.