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Sökning: WFRF:(Leboyer M)

  • Resultat 21-30 av 61
  • Föregående 12[3]4567Nästa
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21.
  • Amare, Azmeraw T, et al. (författare)
  • Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.
  • 2018
  • Ingår i: JAMA psychiatry. - 2168-6238. ; 75:1, s. 65-74
  • Tidskriftsartikel (refereegranskat)abstract
    • Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
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22.
  • Li, M., et al. (författare)
  • Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance
  • 2016
  • Ingår i: British Journal of Psychiatry. - 0007-1250. ; 208:2, s. 128-137
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Bipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain. We sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL. To detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 577 5) and cognitive performance (n = 342) among healthy individuals. Integrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P=5.85 x 10(-5)). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P=3.54 x 10(-8)). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals. Our findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.
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25.
  • Li, M, et al. (författare)
  • Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.
  • 2014
  • Ingår i: Molecular psychiatry. - 1476-5578. ; 19:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64 888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10−5, odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10−6). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
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26.
  • Pinto, Dalila, et al. (författare)
  • Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.
  • 2014
  • Ingår i: American journal of human genetics. - 1537-6605. ; 94:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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29.
  • Anney, Richard, et al. (författare)
  • A genome-wide scan for common alleles affecting risk for autism.
  • 2010
  • Ingår i: Human Molecular Genetics. - 0964-6906. ; 19:20, s. 4072-4082
  • Tidskriftsartikel (refereegranskat)abstract
    • Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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30.
  • Anney, Richard, et al. (författare)
  • Individual common variants exert weak effects on the risk for autism spectrum disorders.
  • 2012
  • Ingår i: Human Molecular Genetics. - 0964-6906. ; 21:21, s. 4781-92
  • Tidskriftsartikel (refereegranskat)abstract
    • While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
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  • Resultat 21-30 av 61
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