Schizophrenia is a heritable disorder with substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder.

Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination of effector stimulation after G protein receptor activation. RGS9-2, a brain-specific splice variant of the RGS9 gene, is highly enriched in striatum and also expressed at much lower levels in periaqueductal gray and spinal cord, structures known to mediate various actions of morphine and other opiates. Morphine exerts its acute rewarding and analgesic effects by activation of inhibitory guanine nucleotide-binding regulatory protein-coupled opioid receptors, whereas chronic morphine causes addiction, tolerance to its acute analgesic effects, and profound physical dependence by sustained activation of these receptors. We show here that acute morphine administration increases expression of RGS9-2 in NAc and the other CNS regions, whereas chronic exposure decreases RGS9-2 levels. Mice lacking RGS9 show enhanced behavioral responses to acute and chronic morphine, including a dramatic increase in morphine reward, increased morphine analgesia with delayed tolerance, and exacerbated morphine physical dependence and withdrawal. These findings establish RGS9 as a potent negative modulator of opiate action in vivo, and suggest that opiate-induced changes in RGS9 levels contribute to the behavioral and neural plasticity associated with chronic opiate administration. R egulators of G protein signaling (RGS) share a 130-aa RGS (GTPase-activating) domain, which binds to the GTP-bound form of G␣i or G␣q and accelerates the termination of effector stimulation (1-3). RGS proteins are thereby thought to repress the signaling efficacy of receptors coupled to these G proteins. In addition, many of the 25 mammalian RGS proteins known to date contain domains that provide them with additional anchoring or scaffolding properties (4-6). Thus, the net effect of RGS proteins on G protein-coupled receptor signaling in vivo may be complicated and difficult to ascertain from in vitro studies alone.In brain, RGS proteins show distinct regional and cellular distributions (7). A prominent example is RGS9, which exists in two forms, RGS9-1 and RGS9-2, that are generated by alternative splicing (8, 9). These proteins differ at their C terminus only, with RGS9-1 containing 18 unique C-terminal amino acids and RGS9-2 containing 209 unique C-terminal amino acids. RGS9-1 is expressed solely in retina, where it is implicated in regulating phototransduction (9, 10). By contrast, RGS9-2 is expressed solely in brain, where it shows a distinctive pattern of expression in brain regions important for the actions of opiate drugs (7,8). RGS9-2 is highly enriched in striatum (including the ventral striatum or nucleus accumbens, NAc), a region important for opiate reward, but is also present at much lower levels in periaqueductal gray and spinal cord, structures important for opiate analgesia (11).We have demonstrated previously that RGS9-2 can negatively modulate opioid receptor function in cultured Xenopus melanophores in vitro (8,12). These findings, coupled with...

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10−8) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52–0.73; P-value = 9.62 × 10−9). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55–0.76, P-value = 3.25 × 10−8). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.

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