27 research outputs found
Occupational exposure to pesticides increases the risk of incident AD: The Cache County Study
Genome-wide association of mood-incongruent psychotic bipolar disorder
Mood-incongruent psychotic features (MICP) are familial symptoms of bipolar disorder (BP) that also occur in schizophrenia (SZ), and may represent manifestations of shared etiology between the major psychoses. In this study we have analyzed three large samples of BP with imputed genome-wide association data and have performed a meta-analysis of 2196 cases with MICP and 8148 controls. We found several regions with suggestive evidence of association (P<10(-6)), although no marker met genome-wide significance criteria. The top associations were on chromosomes: 6q14.2 within the PRSS35/SNAP91 gene complex (rs1171113, P=9.67 × 10(-8)); 3p22.2 downstream of TRANK/LBA1 (rs9834970, P=9.71 × 10(-8)); and 14q24.2 in an intron of NUMB (rs2333194, P=7.03 × 10(-7)). These associations were present in all three samples, and both rs1171113 and rs2333194 were found to be overrepresented in an analysis of MICP cases compared with all other BP cases. To test the relationship of MICP with SZ, we performed polygenic analysis using the Psychiatric GWAS Consortium SZ results and found evidence of association between SZ polygenes and the presence of MICP in BP cases (meta-analysis P=0.003). In summary, our analysis of the MICP phenotype in BP has provided suggestive evidence for association of common variants in several genes expressed in the nervous system. The results of our polygenic analysis provides support for a modest degree of genetic overlap between BP with MICP and SZ, highlighting that phenotypic correlations across syndromes may be due to the influence of polygenic risk factors
The 32-year relationship between cholesterol and dementia from midlife to late life(e–Pub ahead of print)
No advantage of Aβ 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies
10.1212/01.wnl.0000313933.17796.f6Neurology70242291-2298NEUR
Genome-wide significant association between a 'negative mood delusions' dimension in bipolar disorder and genetic variation on chromosome 3q26.1
Research suggests that clinical symptom dimensions may be more useful in delineating the genetics of bipolar disorder (BD) than standard diagnostic models. To date, no study has applied this concept to data from genome-wide association studies (GWAS). We performed a GWAS of factor dimensions in 927 clinically well-characterized BD patients of German ancestry. Rs9875793, which is located in an intergenic region of 3q26.1 and in the vicinity of the solute carrier family 2 (facilitated glucose transporter), member 2 gene (SLC2A2), was significantly associated with the factor analysis-derived dimension 'negative mood delusions' (n=927; P=4.65 × 10(-8), odds ratio (OR)=2.66). This dimension was comprised of the symptoms delusions of poverty, delusions of guilt and nihilistic delusions. In case-control analyses, significant association with the G allele of rs9875793 was only observed in the subgroup of BD patients who displayed symptoms of 'negative mood delusions' (allelic χ(2) model: P(G)=0.0001, OR=1.92; item present, n=89). Further support for the hypothesis that rs9875793 is associated with BD in patients displaying 'negative mood delusions' symptom, such as delusions of guilt, was obtained from an European American sample (GAIN/TGEN), which included 1247 BD patients and 1434 controls (P(EA)=0.028, OR=1.27)
Genome-Wide Association Analysis of Age at Onset and Psychotic Symptoms in Bipolar Disorder
Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles
Supplementary Material for: Assessment of Whole-Exome Sequence Data in Attempted Suicide within a Bipolar Disorder Cohort
<p>Suicidal behavior is a complex and devastating phenotype with a
heritable component that has not been fully explained by existing common
genetic variant analyses. This study represents the first large-scale
DNA sequencing project designed to assess the role of rare functional
genetic variation in suicidal behavior risk. To accomplish this,
whole-exome sequencing data for ∼19,000 genes were generated for 387
bipolar disorder subjects with a history of suicide attempt and 631
bipolar disorder subjects with no prior suicide attempts. Rare
functional variants were assessed in all exome genes as well as pathways
hypothesized to contribute to suicidal behavior risk. No result
survived conservative Bonferroni correction, though many suggestive
findings have arisen that merit additional attention. In addition,
nominal support for past associations in genes, such as <i>BDNF</i>, and
pathways, such as the hypothalamic-pituitary-adrenal axis, was also
observed. Finally, a novel pathway was identified that is driven by
aldehyde dehydrogenase genes. Ultimately, this investigation explores
variation left largely untouched by existing efforts in suicidal
behavior, providing a wealth of novel information to add to future
investigations, such as meta-analyses.</p