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Schizophrenia is a highly heritable, severe psychiatric disorder affecting approximately 1% of the world population. A substantial portion of heritability is still unexplained and the pathophysiology of schizophrenia remains to be elucidated. To identify more schizophrenia susceptibility loci, we performed a genome-wide association study (GWAS) on 498 patients with schizophrenia and 2025 controls from the Han Chinese population, and a follow-up study on 1027 cases and 1005 controls. In the follow-up study, we included 384 single nucleotide polymorphisms (SNPs) which were selected from the top hits in our GWAS (130 SNPs) and from previously implicated loci for schizophrenia based on the SZGene database, NHGRI GWAS Catalog, copy number variation studies, GWAS meta-analysis results from the international Psychiatric Genomics Consortium (PGC) and candidate genes from plausible biological pathways (254 SNPs).Within the chromosomal region Xq28, SNP rs2269372 in RENBP achieved genome-wide significance with a combined P value of 3.98×10−8 (OR of allele A = 1.31). SNPs with suggestive P values were identified within 2 genes that have been previously implicated in schizophrenia, MECP2 (rs2734647, Pcombined = 8.78×10−7, OR = 1.28; rs2239464, Pcombined = 6.71×10−6, OR = 1.26) and ARHGAP4 (rs2269368, Pcombined = 4.74×10−7, OR = 1.25). In addition, the patient sample in our follow-up study showed a significantly greater burden for pre-defined risk alleles based on the SNPs selected than the controls. This indicates the existence of schizophrenia susceptibility loci among the SNPs we selected. This also further supports multigenic inheritance in schizophrenia. Our findings identified a new schizophrenia susceptibility locus on Xq28, which harbor the genes RENBP, MECP2, and ARHGAP4. [ABSTRACT FROM PUBLISHER]

Objective: The purpose of this study was to find loci for major depression via linkage analysis of a large sibling pair sample. Method: The authors conducted a genome-wide linkage analysis of 839 families consisting of 971 affected sibling pairs with severe recurrent major depression, comprising waves I and II of the Depression Network Study cohort. In addition to examining affected status, linkage analyses in the full data set were performed using diagnoses restricted by impairment severity, and association mapping of hits in a large case-control data set was attempted. Results: The authors identified genomewide significant linkage to chromosome 3p25-26 when the diagnoses were restricted by severity, which was a maximum LOD score of 4.0 centered at the linkage marker D3S1515. The linkage signal identified was genome-wide significant after correction for the multiple phenotypes tested, although subsequent association mapping of the region in a genome-wide association study of a U.K. depression sample did not provide significant results. Conclusions: The authors report a genome-wide significant locus for depression that implicates genes that are highly plausible for involvement in the etiology of recurrent depression. Despite the fact that association mapping in the region was negative, the linkage finding was replicated by another group who found genome-wide-significant linkage for depression in the same region. This suggests that 3p25-26 is a new locus for severe recurrent depression. This represents the first report of a genome-wide significant locus for depression that also has an independent genome-wide significant replication. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries.Methods: We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10(-7)Findings: After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10(-6); odds ratio [OR] 1·39, 95% CI 1·21-1·59) and rs2814707 (p=3·32×10(-6); 1·38, 1·20-1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10(-10); OR 1·22, 95% CI 1·15-1·30) and rs2814707 (p=4·72×10(-10); 1·22, 1·15-1·30) were associated with ALS.Interpretation: We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene. [ABSTRACT FROM AUTHOR]