In This Issue – October 15th| Volume 72, ISSUE 8, P613-614, October 15, 2012

A brief summary of the articles appearing in this issue of Biological Psychiatry

        Genome-wide Analyses: Linkage and Association

        Previous genome-wide association studies (GWAS) have implicated the major histocompatibility complex (MHC) region in schizophrenia susceptibility. Here, the Irish Schizophrenia Genomics Consortium and the Wellcome Trust Case Control Consortium 2 (pages 620–628) identify an association with the human leukocyte antigen classical allele HLA-C*01:02 at the MHC locus in Irish and United Kingdom populations. They also replicate association with two reported protective alleles and suggest that these alleles tag the same association signal. These findings lend further support for the involvement of the MHC region in schizophrenia susceptibility.
        Obsessive-compulsive disorder (OCD) has a complex etiology involving both genetic and environmental factors. Mathews et al. (pages 629–636) examined Caucasian families with childhood-onset OCD using genome-wide linkage approaches. They identified five areas of interest, with the strongest evidence for linkage on chromosome 1p36. This finding suggests that chromosome 1p36 may harbor one or more susceptibility genes for OCD.
        There is a genetic component to cannabis dependence, but susceptibility genes remain largely unknown. Han et al. (pages 637–644) employed a multi-stage design to identify genetic variants underlying cannabis dependence. In the linkage analysis stage, the strongest signal was identified in African-Americans on chromosome 8p21. Then using a GWAS dataset, they identified one single nucleotide polymorphism (SNP) at NRG1 that showed consistent evidence for association in both African-Americans and European-Americans. They replicated the association of this variant in an independent sample of African-Americans, suggesting that NRG1 may be a susceptibility gene for cannabis dependence.
        GWAS have implicated polymorphisms at chromosome 3p21.1, including rs2251219 in PBRM1, in the susceptibility to bipolar disorder. Using data from seven European cohorts and confirmed with a meta-analysis, Vassos et al. (pages 645–650) replicate the association of rs2251219 with bipolar disorder. Using a separate data set, they did not confirm association with schizophrenia, in contrast to previous reports that it is also a risk marker for psychosis.

        Copy Number Variations in Brain DNA

        Copy number variations (CNVs) have been associated with neurodevelopmental behavioral disorders, but prior work has used peripheral cells or transformed cell lines. Ye et al. (pages 651–654) analyzed brain DNA from patients and controls for evidence of previously reported CNVs and increased genome-wide CNV burden and also explored gene expression within CNVs. They found that certain recurrent CNVs were present in a small percentage of patients with various psychiatric diagnoses and report evidence for incomplete molecular penetrance of some CNVs. No evidence of greater CNV burden was detected in patients with schizophrenia or mood disorders.

        Imaging Genetics in Psychiatry

        Tumor necrosis factor (TNF), a cytokine involved in inflammatory processes, has been linked to multiple neuropsychiatric disorders, including depression and Alzheimer's disease. Baune et al. (pages 655–662) investigated genetic variants of TNF and their effects on brain structure as measured with voxel-based morphometry in healthy participants. They found that certain TNF genotypes were associated with reduced bilateral hippocampus volumes, indicating that these variants play a role in neurodegeneration.
        Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and its receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) have been implicated in mood disorders. Using diffusion tensor imaging, Murphy et al. (pages 663–670) found that rs11140714, a NTRK2 polymorphism, impacts white matter connections in several brain regions, but particularly in the cingulum, in patients with major depressive disorder (MDD) compared to control subjects. NTRK2 variants appear to increase risk of microstructural abnormalities in brain regions involved in emotion regulation.
        Darki et al. (pages 671–676) assessed the effect of dyslexia genes on white matter structure and found that polymorphisms of rs3743204 (DYX1C1), rs793842 (DCDC2) and rs6935076 (KIAA0319) significantly affect white matter volume in the left temporo-parietal region in a normal population of children and adolescents. They also report that white matter volume influenced reading ability. The finding links previous neuroimaging and genetic results in both normal and impaired readers, and the identified temporo-parietal connectivity suggests a mechanism underlying variability in reading ability.
        Genetic vulnerability to cognitive decline is well documented and the sodium channel gene SCN1A has been associated with cognitive processes and cortical function. Meier et al. (pages 677–683) investigated interactive effects of an SCN1A variant and age on frontal and posterior cingulate cortex activity in healthy volunteers. They found reduced gray matter density and an age-related increase in activation in carriers of the vulnerability allele, suggesting that SCN1A exhibits an effect on cortical aging processes and brain morphology.

        Cortical N-acetylaspartate in 22q11.2 Deletion Syndrome

        Children with 22q11.2 deletion syndrome have learning difficulties and a high risk of mental illness. Shashi et al. (pages 684–691) investigated neurometabolites in the dorsolateral prefrontal cortex, a critical brain region for cognition, using in vivo proton spectroscopy and found elevated levels of N-acetylaspartate in children with 22q11.2 deletion syndrome compared to healthy controls. Children with elevated levels had higher rates of attention-deficit/hyperactivity disorder and lower overall psychological functioning. These findings indicate that frontal lobe development may be altered in 22q11.2 deletion syndrome.

        Shared Genetic Etiology: Autism Spectrum Disorder and Specific Language Impairment

        Bartlett et al. (pages 692–699) examined families with at least one member each with autism spectrum disorder (ASD) and specific language impairment to evaluate potential shared genetic etiology. They found increases in heritability on several of the language measures when removing ASD subjects from the analysis, indicating unique differential genetic effects. Despite sharing risk loci with specific language impairment individuals, the data indicate that persons with ASD have gene-gene interaction effects that account for differences in behavior.

        Pharmacogenetics: BDNF and Tardive Dyskinesia Treatment

        Low BDNF may play a role in the pathophysiology of tardive dyskinesia (TD). Zhang et al. (pages 700–706) measured BDNF levels and genotyped for BDNF in schizophrenia patients with and without TD and healthy controls. Patients with TD also participated in a double-blind randomized trial of Ginkgo biloba, an antioxidant known to affect BDNF levels. TD patients had lower BDNF levels than non-TD patients and controls. Compared to placebo, Ginkgo biloba treatment improved TD symptoms and increased BDNF levels, effects which were mediated by the Val66Met polymorphism.

        Methods: Estimating Genetic Variance

        Genome-wide association studies of MDD have been unsuccessful in detecting genome-wide significant SNPs. Using genome-wide data from Dutch samples in this Methods paper, Lubke et al. (pages 707–709) applied two recently proposed methods to estimate the variance attributable to SNPs in MDD and four additional phenotypes. All estimates differed significantly from zero. Results show that a substantial proportion of variance in MDD is due to SNPs even when considering the lower bound of the confidence interval.