Linkage Study of Schizophrenia with Markers on Chromosome 11 in Two Japanese Pedigrees

Abstract: We examined the Linkage between schizophrenia and DNA markers on chromosome 11 in two Japanese pedigrees. Thirty individuals from the two pedigrees were genotyped at the eleven polymorphisms (eight loci) studied. Data were analysed according to three models, representing a range of single gene models from near dominant to an intermediate model. For all markers, except those at the D11S35 locus, there is no evidence for the linkage. Positive LOD scores between 1 and 1.5 are obtained for some genetic models with the polymorphism at D11S35. Two point scores for the broad diagnostic model and for the intermediate parameter set peak at 1.49.     

Neurocognitive Performance Stability in a Multiplex Multigenerational Study of Schizophrenia

Certain cognitive measures are heritable and differentiate individuals at risk for schizophrenia from unaffected family members and healthy comparison subjects. These deficits in neurocognitive performance in patients with schizophrenia appear stable in the short-term. However, the duration of most, but not all, longitudinal studies is modest and the majority have relied on traditional average performance measures to examine stability. Using a computerized neurocognitive battery (CNB), we assessed mean performance (accuracy and speed) and intra-individual variability (IIV) in a longitudinal study aimed to examine neurocognitive stability in European-American multiplex families with schizophrenia. Thirty-four patients with schizophrenia, 65 unaffected relatives, and 45 healthy comparison subjects completed the same computerized neurocognitive assessment over approximately 5 years. Measures of mean performance showed that patients had stable accuracy performance but were slower in many neurocognitive domains over time as compared with unaffected family members and healthy subjects. Furthermore, patients and family members showed dissociable patterns of change in IIV for speed across cognitive domains: compared with controls, patients showed higher across-task IIV in performance compared with family members, who showed lower across-task IIV. Patients showed an increase in IIV over time, whereas family members showed a decrease. These findings suggest that measures of mean performance and IIV of speed during a CNB may provide useful information about the genetic susceptibility in schizophrenia.Key words: intra-individual variability, schizophrenia, cognition, family     

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans

BackgroundSchizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world’s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. MethodsWe performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. ResultsOur primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10^–30) and African American (P < .0005) participants in CSP #572. ConclusionsWe have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.     

Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes

Cognitive impairments are a core feature in patients with schizophrenia. These deficits could serve as effective tools for understanding the genetic architecture of schizophrenia. This study investigated whether genetic variants associated with cognitive impairments aggregate in functional gene networks related to the pathogenesis of schizophrenia. Here, genome-wide association studies (GWAS) of a range of cognitive phenotypes relevant to schizophrenia were performed in 411 healthy subjects. We attempted to replicate the GWAS data using 257 patients with schizophrenia and performed a meta-analysis of the GWAS findings and the replicated results. Because gene networks, rather than a single gene or genetic variant, may be strongly associated with the susceptibility to schizophrenia and cognitive impairments, gene-network analysis for genes in close proximity to the replicated variants was performed. We observed nominal associations between 3054 variants and cognitive phenotypes at a threshold of P < 1.0 × 10^{− 4}. Of the 3054 variants, the associations of 191 variants were replicated in the replication samples (P < .05). However, no variants achieved genome-wide significance in a meta-analysis (P > 5.0 × 10^{− 8}). Additionally, 115 of 191 replicated single nucleotide polymorphisms (SNPs) have genes located within 10 kb of the SNPs (60.2%). These variants were moderately associated with cognitive phenotypes that ranged from P = 2.50 × 10^{− 5} to P = 9.40 × 10^{− 8}. The genes located within 10 kb from the replicated SNPs were significantly grouped in terms of glutamate receptor activity (false discovery rate (FDR) q = 4.49 × 10^{− 17}) and the immune system related to major histocompatibility complex class I (FDR q = 8.76 × 10^{− 11}) networks. Our findings demonstrate that genetic variants related to cognitive trait impairment in schizophrenia are involved in the N-methyl-d-aspartate glutamate network.Key words: schizophrenia, genome-wide association study, cognitive phenotypes, glutamate receptor activity, immune function, functional gene network     

Genome-Wide Association Study of the Relationship Between Matrix Metalloproteinases and Intracranial Aneurysms

Background and PurposeMatrix metalloproteinases (MMPs) are expected to play an important role in extracellular matrix (ECM) remodeling in response to hemodynamic stress. We investigated the association between MMPs and intracranial aneurysms (IAs) via a genome-wide association study (GWAS) of IAs.MethodsA GWAS data set of 250 IAs and 294 controls was used to analyze the genetic link between MMPs and IAs via single-nucleotide polymorphisms (SNPs), MMP gene families, and in silico functional analyses of gene ontology (GO) enrichment and protein–protein interaction (PPI).ResultsForty-eight SNPs and 1 indel out of 342 markers of MMP genes were related to IAs. The rs2425024 SNP located on MMP24 was the most strongly associated with IAs (OR=0.43, CI=0.30–0.61, p=2.4×10^-6), suggesting a protective effect. The 16938619 SNP of MMP26 significantly increased the risk of an IA (OR=3.12, 95% CI=1.76–5.50, p=8.85×10^-5). Five MMP genes (MMP24, MMP13, MMP2, MMP17, and MMP1) increased the susceptibility to an IA. MMP24 was the gene most closely related to IAs (p=7.96×10^-7). GO analysis showed that collagen catabolism was the most-enhanced biological process. Further, metalloendopeptidase activity and ECM were predominantly detected in the cellular component and molecular function, respectively. PPI provided evidence that MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), and TIMP3 genes constitute a network for predicting IA formation.ConclusionsThe present results provide comprehensive insight into the occurrence of IAs associated with MMPs.     

Susceptibility Genes for Multiple Sclerosis Identified in a Gene-Based Genome-Wide Association Study

Background and Purpose

Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. The aim of this study was to identify more genes associated with MS.

Methods

Based on the publicly available data of the single-nucleotide polymorphism-based genome-wide association study (GWAS) from the database of Genotypes and Phenotypes, we conducted a powerful gene-based GWAS in an initial sample with 931 family trios, and a replication study sample with 978 cases and 883 controls. For interesting genes, gene expression in MS-related cells between MS cases and controls was examined by using publicly available datasets.

Results

A total of 58 genes was identified, including 20 "novel" genes significantly associated with MS (p<1.40×10^-4). In the replication study, 44 of the 58 identified genes had been genotyped and 35 replicated the association. In the gene-expression study, 21 of the 58 identified genes exhibited differential expressions in MS-related cells. Thus, 15 novel genes were supported by replicated association and/or differential expression. In particular, four of the novel genes, those encoding myelin oligodendrocyte glycoprotein (MOG), coiled-coil alpha-helical rod protein 1 (CCHCR1), human leukocyte antigen complex group 22 (HCG22), and major histocompatibility complex, class II, DM alpha (HLA-DMA), were supported by the evidence of both.

Conclusions

The results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS. The novel genes identified herein may provide new insights into the molecular genetic mechanisms underlying MS.     

Association Study Between the Pericentrin (PCNT) Gene and Schizophrenia

Disrupted-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia (SZ) and major depressive disorder (MDD), interacts with several proteins and some of them are reported to be genetically associated with SZ. Pericentrin (PCNT) also interacts with DISC1 and recently single-nucleotide polymorphisms (SNPs) within the PCNT gene have been found to show significant associations with SZ and MDD. In this study, case-controlled association analysis was performed to determine if the PCNT gene is implicated in SZ. Nine SNPs were analyzed in 1,477 individuals (726 patients with SZ and 751 healthy controls). No significant difference was observed between the controls and the patients in allelic frequencies or genotypic distributions of eight SNPs. Although allelic distribution of rs11702684 was different between the two groups (P = 0.042), the difference did not reach statistical significance after permutation correction for multiple comparisons. In the haplotypic analysis, we could not find any significant association in our subjects, either. This gene may not play a major role independently in the etiology of SZ in the Japanese population.