CACNA1C hypermethylation is associated with bipolar disorder

The CACNA1C gene, encoding a subunit of the L-type voltage-gated calcium channel is one of the best-supported susceptibility genes for bipolar disorder (BD). Genome-wide association studies have identified a cluster of non-coding single-nucleotide polymorphisms (SNPs) in intron 3 to be highly associated with BD and schizophrenia. The mechanism by which these SNPs confer risk of BD appears to be through an altered regulation of CACNA1C expression. The role of CACNA1C DNA methylation in BD has not yet been addressed. The aim of this study was to investigate if CACNA1C DNA methylation is altered in BD. First, the methylation status of five CpG islands (CGIs) across CACNA1C in blood from BD subjects (n=40) and healthy controls (n=38) was determined. Four islands were almost completely methylated or completely unmethylated, while one island (CGI 3) in intron 3 displayed intermediate methylation levels. In the main analysis, the methylation status of CGI 3 was analyzed in a larger sample of BD subjects (n=582) and control individuals (n=319). Out of six CpG sites that were investigated, five sites showed significant hypermethylation in cases (lowest P=1.16 × 10(-7) for CpG35). Nearby SNPs were found to influence the methylation level, and we identified rs2238056 in intron 3 as the strongest methylation quantitative trait locus (P=2.6 × 10(-7)) for CpG35. In addition, we found an increased methylation in females, and no difference between bipolar I and II. In conclusion, we find that CACNA1C methylation is associated with BD and suggest that the regulatory effect of the non-coding risk variants involves a shift in DNA methylation

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder

Linkage disequilibrium mapping of a breast cancer susceptibility locus near RAI/PPPIRI3L/iASPP

Background: Previous results have suggested an association of the region of 19q13.3 with several forms of cancer. In the present study, we investigated 27 public markers within a previously identified 69 kb stretch of chromosome 19q for association with breast cancer by using linkage disequilibrium mapping. The study groups included 434 postmenopausal breast cancer cases and an identical number of individually matched controls. Methods and Results: Studying one marker at a time, we found a region spanning the gene RAI ( alias PPP1R13L or iASPP) and the 5' portion of XPD to be associated with this cancer. The region corresponds to a haplotype block, in which there seems to be very limited recombination in the Danish population. Studying combinations of markers, we found that two to four neighboring markers gave the most consistent and strongest result. The haplotypes with strongest association with cancers were located in the gene RAI and just 3' to the gene. Coinciding peaks were seen in the region of RAI in groups of women of different age. In a follow-up to these results we sequenced 10 cases and 10 controls in a 44 kb region spanning the peaks of association. This revealed 106 polymorphisms, many of which were not in the public databases. We tested an additional 44 of these for association with disease and found a new tandem repeat marker, called RAI-3' d1, located downstream of the transcribed region of RAI, which was more strongly associated with breast cancer than any other marker we have tested (RR = 2.44 (1.41 - 4.23, p = 0.0008, all cases; RR = 6.29 (1.49 - 26.6), p = 0.01, cases up to 55 years of age). Conclusion: We expect the marker RAI-3' d1 to be (part of) the cause for the association of the chromosome 19q13.3 region's association with cancer

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10 -6) and rs8057927 in CDH13 (P=1.39 × 10 -5). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10 -7). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10 -7). This signal was replicated in the follow-up analysis (P=2.3 × 10 -2). Significant interaction with maternal CMV infection was found for rs7902091 (P SNP × CMV =7.

The Etiology of Multiple Sclerosis: Genetic Evidence for the Involvement of the Human Endogenous Retrovirus HERV-Fc1

We have investigated the role of human endogenous retroviruses in multiple sclerosis by analyzing the DNA of patients and controls in 4 cohorts for associations between multiple sclerosis and polymorphisms near viral restriction genes or near endogenous retroviral loci with one or more intact or almost-intact genes. We found that SNPs in the gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis

Association between genes on chromosome 19p13.2 and panic disorder

Panic disorder (PD) is a severe and disabling mental disorder, which is moderately heritable. In a previous study, we carried out a genome-wide association study using patients with PD and control individuals from the isolated population of the Faroe Islands and identified chromosome 19p13.2 as a candidate region. To further investigate this chromosomal region for association with PD, we analysed eight single nucleotide polymorphisms (SNPs) in three candidate genes - small-nuclear RNA activating complex, polypeptide 2 (SNAPC2), mitogen-activated protein kinase kinase 7 (MAP2K7) and leucine-rich repeat containing 8 family, member E (LRRC8E) - these genes have previously been directly or indirectly implicated in other mental disorders. A total of 511 patients with PD and 1029 healthy control individuals from the Faroe Islands, Denmark and Germany were included in the current study. SNPs covering the gene region of SNAPC2, MAP2K7 and LRRC8E were genotyped and tested for association with PD. In the Faroese cohort, rs7788 within SNAPC2 was significantly associated with PD, whereas rs3745383 within LRRC8E was nominally associated. No association was observed between the analysed SNPs and PD in the Danish cohorts. In the German women, we observed a nominal association between rs4804833 within MAP2K7 and PD. We present further evidence that chromosome 19p13.2 may harbour candidate genes that contribute towards the risk of developing PD. Moreover, the implication of the associated genes in other mental disorders may indicate shared genetic susceptibility between mental disorders. We show that associated variants may be sex specific, indicating the importance of carrying out a sex-specific association analysis of PD. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved

Are TMEM genes potential candidate genes for panic disorder?

We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12, a previously reported candidate region for PD. Three single nucleotide polymorphisms (rs887231, rs887230 and rs4795942) located upstream and within TMEM132E showed a nominal significant association with PD primarily in the Danish cohort. No nominal significant associations were observed between TMEM98 and PD. Our data indicate that TMEM132E might contribute moderately towards the risk of developing PD