451 research outputs found
Genome-wide association study of cognitive flexibility assessed by the Wisconsin Card Sorting Test
Excess of homozygosity in the major histocompatibility complex in schizophrenia
Genome-wide association studies (GWAS) in schizophrenia have focused on additive allelic effects to identify disease risk loci. In order to examine potential recessive effects, we applied a novel approach to identify regions of excess homozygosity in an ethnically homogenous cohort: 904 schizophrenia cases and 1640 controls drawn from the Ashkenazi Jewish (AJ) population. Genome-wide examination of runs of homozygosity identified an excess in cases localized to the major histocompatibility complex (MHC). To refine this signal, we used the recently developed GERMLINE algorithm to identify chromosomal segments shared identical-by-descent (IBD) and compared homozygosity at such segments in cases and controls. We found a significant excess of homozygosity in schizophrenia cases compared with controls in the MHC (P-value = 0.003). An independent replication cohort of 548 schizophrenia cases from Japan and 542 matched healthy controls demonstrated similar effects. The strongest case-control recessive effects (P = 8.81 x 10(-8)) were localized to a 53-kb region near HLA-A, in a segment encompassing three poorly annotated genes, TRIM10, TRIM15 and TRIM40. At the same time, an adjacent segment in the Class IMHC demonstrated clear additive effects on schizophrenia risk, demonstrating the complexity of association in the MHC and the ability of our IBD approach to refine localization of broad signals derived from conventional GWAS. In sum, homozygosity in the classical MHC region appears to convey significant risk for schizophrenia, consistent with the ecological literature suggesting that homozygosity at the MHC locus may be associated with vulnerability to disease
Antipsychotic Treatment and Functional Connectivity of the Striatum in First-Episode Schizophrenia
IMPORTANCE Previous evidence has implicated corticostriatal abnormalities in the pathophysiology of psychosis. Although the striatum is the primary target of all efficacious antipsychotics, the relationship between its functional connectivity and symptomatic reduction remains unknown. OBJECTIVE To explore the longitudinal effect of treatment with second-generation antipsychotics on functional connectivity of the striatum during the resting state in patients experiencing a first episode of psychosis. DESIGN, SETTING, AND PARTICIPANTS This prospective controlled study took place at a clinical research center and included 24 patients with first-episode psychosis and 24 healthy participants matched for age, sex, education, and handedness. Medications were administered in a double-blind randomized manner. INTERVENTIONS Patients were scanned at baseline and after 12 weeks of treatment with either risperidone or aripiprazole. Their symptoms were evaluated with the Brief Psychiatric Rating Scale at baseline and follow-up. Healthy participants were scanned twice within a 12-week interval. MAIN OUTCOMES AND MEASURES Functional connectivity of striatal regions was examined via functional magnetic resonance imaging using a seed-based approach. Changes in functional connectivity of these seeds were compared with reductions in ratings of psychotic symptoms. RESULTS Patients had a median exposure of 1 day to antipsychotic medication prior to being scanned (mean [SD] = 4.5 [6.1]). Eleven patients were treated with aripiprazole and 13 patients were treated with risperidone. As psychosis improved, we observed an increase in functional connectivity between striatal seed regions and the anterior cingulate, dorsolateral prefrontal cortex, and limbic regions such as the hippocampus and anterior insula (P \u3c .05, corrected for multiple comparisons). Conversely, a negative relationship was observed between reduction in psychosis and functional connectivity of striatal regions with structures within the parietal lobe (P \u3c .05, corrected for multiple comparisons). CONCLUSIONS AND RELEVANCE Our results indicated that corticostriatal functional dysconnectivity in psychosis is a state-dependent phenomenon. Increased functional connectivity of the striatum with prefrontal and limbic regions may be a biomarker for improvement in symptoms associated with antipsychotic treatment
The SORL1 gene and convergent neural risk for Alzheimer\u27s disease across the human lifespan
Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer\u27s disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer\u27s risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer\u27s phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n = 118, age 18-86; n = 68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n = 269, age 0-92) and (3) Alzheimer\u27s neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer\u27s individuals (n = 710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan
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COMT genetic variation confers risk for psychotic and affective disorders: a case control study
BACKGROUND: Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. We hypothesized that COMT variation may confer a general risk for psychiatric disorders and have genotyped four COMT variants (Val158Met, rs737865, rs165599, and a SNP in the P2 promoter [-278A/G; rs2097603]) in 394 Caucasian cases and 467 controls. Cases included patients with schizophrenia (n = 196), schizoaffective disorder (n = 62), bipolar disorder (n = 82), major depression (n = 30), and patients diagnosed with either psychotic disorder NOS or depressive disorder NOS (n = 24). RESULTS: SNP rs2097603, the Val/Met variant and SNP rs165599 were significantly associated (p = 0.004; p = 0.05; p = 0.035) with a broad "all affected" diagnosis. Haplotype analysis revealed a potentially protective G-A-A-A haplotype haplotype (-278A/G; rs737865; Val108/158Met; rs165599), which was significantly underrepresented in this group (p = 0.0033) and contained the opposite alleles of the risk haplotype previously described by Shifman et al. Analysis of diagnostic subgroups within the "all affecteds group" showed an association of COMT in patients with psychotic disorders as well as in cases with affective illness although the associated variants differed. The protective haplotype remained significantly underrepresented in most of these subgroups. CONCLUSION: Our results support the view that COMT variation provides a weak general predisposition to neuropsychiatric disease including psychotic and affective disorders
Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes
The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 x 10(-56)), MAPT (OR = 0.62, P = 1.78 x 10(-11)) and GBA (multiple distinct haplotypes, OR \u3e 8.28, P = 1.13 x 10(-11) and OR = 2.50, P = 1.22 x 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 x 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts
Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote\u27s two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 x 10(-12); T1D, P = 2.4 x 10(-10); psoriasis, P = 5.9 x 10(-6); celiac disease, P = 1.2 x 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 x 10(-3); T1D, P = 8.6 x 10(-27); celiac disease, P = 6.0 x 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model
Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: Evidence of epistasis and competitive binding
DISC1 influences susceptibility to psychiatric disease and related phenotypes. Intact functions of DISC1 and its binding partners, NDEL1 and NDE1, are critical to neurodevelopmental processes aberrant in schizophrenia (SZ). Despite evidence of an NDEL1–DISC1 protein interaction, there have been no investigations of the NDEL1 gene or the relationship between NDEL1 and DISC1 in SZ. We genotyped six NDEL1 single-nucleotide polymorphisms (SNPs) in 275 Caucasian SZ patients and 200 controls and tested for association and interaction between the functional SNP Ser704Cys in DISC1 and NDEL1. We also evaluated the relationship between NDE1 and DISC1 genotype and SZ. Finally, in a series of in vitro assays, we determined the binding profiles of NDEL1 and NDE1, in relation to DISC1 Ser704Cys. We observed a single haplotype block within NDEL1; the majority of variation was captured by NDEL1 rs1391768. We observed a significant interaction between rs1391768 and DISC1 Ser704Cys, with the effect of NDEL1 on SZ evident only against the background of DISC1 Ser704 homozygosity. Secondary analyses revealed no direct relationship between NDE1 genotype and SZ; however, there was an opposite pattern of risk for NDE1 genotype when conditioned on DISC1 Ser704Cys, with NDE1 rs3784859 imparting a significant effect but only in the context of a Cys-carrying background. In addition, we report opposing binding patterns of NDEL1 and NDE1 to Ser704 versus Cys704, at the same DISC1 binding domain. These data suggest that NDEL1 significantly influences risk for SZ via an interaction with DISC1. We propose a model where NDEL1 and NDE1 compete for binding with DISC1
Functional variants in the LRRK2 gene confer shared effects on risk for Crohn\u27s disease and Parkinson\u27s disease
Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways
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