Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23–24

We obtained evidence from a large study in Dutch twins (N = 8387) and siblings (N = 2295) that variation in loneliness has a genetic component. The heritability estimate for loneliness, which was assessed as an ordinal trait, was 40% and did not differ between males and females. There were 682 sibling pairs with genotypic (around 400 microsatellite markers) data. We combined phenotypic and genotypic data to carry out a genome scan to localize QTLs for loneliness. One region on chromosome 12q23.3-24.3, showed near suggestive linkage. Genetic association tests within this region revealed significant association (p-value 0.009) with one of the alleles of marker D12S79 and with one of the alleles of neighbouring marker D12S395 (p-value 0.043). We review evidence for linkage in this region for psychiatric disorders and discuss our findings within this context. © 2006 Springer Science+Business Media, Inc

Association analyses of the interaction between the ADSS and ATM genes with schizophrenia in a Chinese population

<p>Abstract</p> <p>Background</p> <p>The blood-derived RNA levels of the adenylosuccinate synthase (<it>ADSS</it>) and ataxia telangiectasia mutated (<it>ATM</it>) genes were found to be down- and up-regulated, respectively, in schizophrenics compared with controls, and <it>ADSS </it>and <it>ATM </it>were among eight biomarker genes to discriminate schizophrenics from normal controls. ADSS catalyzes the first committed step of AMP synthesis, while ATM kinase serves as a key signal transducer in the DNA double-strand breaks response pathway. It remains unclear whether these changes result from mutations or polymorphisms in the two genes.</p> <p>Methods</p> <p>Six SNPs in the <it>ADSS </it>gene and three SNPs in the <it>ATM </it>gene in a Chinese population of 488 schizophrenics and 516 controls were genotyped to examine their association with schizophrenia (SZ). Genotyping was performed using the Sequenom platform.</p> <p>Results</p> <p>There was no significant difference in the genotype, allele, or haplotype distributions of the nine SNPs between cases and controls. Using the Multifactor Dimensionality Reduction (MDR) method, we found that the interactions among rs3102460 in the <it>ADSS </it>gene and rs227061 and rs664143 in the <it>ATM </it>gene revealed a significant association with SZ. This model held a maximum testing accuracy of 60.4% and a maximum cross-validation consistency of 10 out of 10.</p> <p>Conclusion</p> <p>These findings suggest that the combined effects of the polymorphisms in the <it>ADSS </it>and <it>ATM </it>genes may confer susceptibility to the development of SZ in a Chinese population.</p

Increased d-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study

An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples

Polymorphisms in the interleukin-10 gene cluster are possibly involved in the increased risk for major depressive disorder

<p>Abstract</p> <p>Background</p> <p>Innate immune inflammatory response is suggested to have a role in the pathogenesis of major depressive disorder (MDD). Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20, and IL-24 are all implicated in the inflammatory processes and polymorphisms in respective genes have been associated with various immunopathological conditions. This study was carried out to investigate whether single-nucleotide polymorphisms (SNPs) in these genes are also associated with MDD.</p> <p>Methods</p> <p>Case-control association study was performed with seven SNPs from the <it>IL10 </it>gene cluster. 153 patients with MDD and 277 healthy control individuals were recruited.</p> <p>Results</p> <p>None of the selected SNPs were individually associated with MDD. The linkage disequilibrium (LD) analysis indicated the existence of two recombination sites in the <it>IL10 </it>gene cluster, thus confirming the formerly established LD pattern of this genomic region. This also created two haplotype blocks, both consisting of three SNPs. Additionally, the haplotype analysis detected a significantly higher frequency of block 2 (<it>IL20 </it>and <it>IL24 </it>genes) haplotype TGC in the patients group compared to healthy control individuals (P = 0.0097).</p> <p>Conclusion</p> <p>Our study established increased risk for MDD related to the <it>IL20 </it>and <it>IL24 </it>haplotype and suggests that cytokines may contribute to the pathogenesis of MDD. Since none of the block 2 SNPs were individually associated with MDD, it is possible that other polymorphisms linked to them contribute to the disease susceptibility. Future studies are needed to confirm the results and to find the possible functional explanation.</p

Effect of the G72 (DAOA) putative risk haplotype on cognitive functions in healthy subjects

<p>Abstract</p> <p>Background</p> <p>In the last years, several susceptibility genes for psychiatric disorders have been identified, among others <it>G72 </it>(also named D-amino acid oxidase activator, DAOA). Typically, the high-risk variant of a vulnerability gene is associated with decreased cognitive functions already in healthy individuals. In a recent study however, a positive effect of the high-risk variant of <it>G72 </it>on verbal working memory was reported. In the present study, we therefore examined the relationship between <it>G72 </it>genotype status and a broad range of cognitive functions in 423 healthy individuals.</p> <p>Methods</p> <p>The <it>G72 </it>carrier status was assessed by the two single nucleotide polymorphisms (SNPs) M23 and M24. Subjects were divided into three risk groups (low, intermediate and high risk).</p> <p>Results</p> <p><it>G72 </it>status influenced a number of cognitive functions, such as verbal working memory, attention, and, at a trend level, spatial working memory and executive functions. Interestingly, the high-risk allele carriers scored better than one or even both other groups.</p> <p>Conclusion</p> <p>Our data show that the putative high-risk haplotype (i.e. homozygote C/C-allele carriers in SNP M23 and homozygote T/T-allele carriers in SNP M24) is in healthy individuals not necessarily associated with worse performance in cognitive functions, but even with better performance in some domains. Further work is required to identify the mechanisms of <it>G72 </it>on brain functions.</p

Ablation of Mrds1/Ofcc1 Induces Hyper-γ-Glutamyl Transpeptidasemia without Abnormal Head Development and Schizophrenia-Relevant Behaviors in Mice

Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as “the Japan Mouse Clinic”. No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia

Transcription Factor SP4 Is a Susceptibility Gene for Bipolar Disorder

The Sp4 transcription factor plays a critical role for both development and function of mouse hippocampus. Reduced expression of the mouse Sp4 gene results in a variety of behavioral abnormalities relevant to human psychiatric disorders. The human SP4 gene is therefore examined for its association with both bipolar disorder and schizophrenia in European Caucasian and Chinese populations respectively. Out of ten SNPs selected from human SP4 genomic locus, four displayed significant association with bipolar disorder in European Caucasian families (rs12668354, p = 0.022; rs12673091, p = 0.0005; rs3735440, p = 0.019; rs11974306, p = 0.018). To replicate the genetic association, the same set of SNPs was examined in a Chinese bipolar case control sample. Four SNPs displayed significant association (rs40245, p = 0.009; rs12673091, p = 0.002; rs1018954, p = 0.001; rs3735440, p = 0.029), and two of them (rs12673091, rs3735440) were shared with positive SNPs from European Caucasian families. Considering the genetic overlap between bipolar disorder and schizophrenia, we extended our studies in Chinese trios families for schizophrenia. The SNP7 (rs12673091, p = 0.012) also displayed a significant association. The SNP7 (rs12673091) was therefore significantly associated in all three samples, and shared the same susceptibility allele (A) across all three samples. On the other hand, we found a gene dosage effect for mouse Sp4 gene in the modulation of sensorimotor gating, a putative endophenotype for both schizophrenia and bipolar disorder. The deficient sensorimotor gating in Sp4 hypomorphic mice was partially reversed by the administration of dopamine D2 antagonist or mood stabilizers. Both human genetic and mouse pharmacogenetic studies support Sp4 gene as a susceptibility gene for bipolar disorder or schizophrenia. The studies on the role of Sp4 gene in hippocampal development may provide novel insights for the contribution of hippocampal abnormalities in these psychiatric disorders

Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach

Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects ($P_{corr}$ = .018, $P_{corr}$ = .015 and $P_{corr}$ = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. Conclusions/Limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies

Comprehensive Gene-Based Association Study of a Chromosome 20 Linked Region Implicates Novel Risk Loci for Depressive Symptoms in Psychotic Illness

Background Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants. Methods We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold-truncated product of P-values for each locus. Results While no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (PempP-value and truncated-product methods, respectively. Conclusions Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci