A Rare Variant in CACNA1D Segregates with 7 Bipolar I Disorder Cases in a Large Pedigree.
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ABSTRACT:
SUBMITTER: Ross J
PROVIDER: S-EPMC5109989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.
| S-EPMC4128749 | biostudies-literature
Project description:BackgroundGenetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.MethodsRare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.ResultsCNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.ConclusionsCNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
| S-EPMC6586545 | biostudies-literature
Project description:Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N=2393, βT-allele=2.33, P-value=1 × 10-4) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N=1604, βT-allele=3.60, P-value=3 × 10-2). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.
| S-EPMC5984098 | biostudies-literature
Project description:Schizophrenia is a severe psychiatric illness that affects ~1% of the population and has a strong genetic underpinning. Recently, genome wide analysis of copy number variation (CNV) has implicated rare and de novo events as important in schizophrenia. Here we report a genome-wide analysis of 245 schizophrenia cases and 490 controls, all of Ashkenazi Jewish descent. Since many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3–1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, as increasing evidence suggests an overlap of specific rare CNVs between autism and schizophrenia. By combining our data with prior CNV studies of schizophrenia and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7,545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with schizophrenia (p = 0.02) and an odds ratio estimate of 17 (95% CI: 1.36–1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior schizophrenia family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for schizophrenia susceptibility.
2010-08-06 | GSE23201 | GEO
Project description:Aim: We previously performed the first trio-based exome study for bipolar disorder and identified 71 de novo mutations. Among these mutations, the only mutation located at the splice donor site was in UNC13B. We focused on and analyzed the functions of the mutation.Methods: In order to analyze the functional alterations, due to the mutation, we performed a minigene splicing assay.Key results: We found that the mutation caused the loss of a wild-type splicing variant, which was consistent with the computational splice prediction, and that an exon-skipping variant increased significantly. The exon-skipping variant also existed in the wild-type minigene, although it was rare. Hence, we validated the expression of the exon-skipping variant using total RNAs derived from the human cerebral cortex. We showed the possibility that the exon-skipping variant was rare, but expressed even in those that do not carry the mutation.Conclusions: Based on our results, we suggest that an abnormal splicing pattern of UNC13B occurred in the patient, which could be related to the pathophysiology of bipolar disorder.
| S-EPMC7292303 | biostudies-literature
Project description:Schizophrenia is a severe psychiatric illness that affects ~1% of the population and has a strong genetic underpinning. Recently, genome wide analysis of copy number variation (CNV) has implicated rare and de novo events as important in schizophrenia. Here we report a genome-wide analysis of 245 schizophrenia cases and 490 controls, all of Ashkenazi Jewish descent. Since many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3–1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, as increasing evidence suggests an overlap of specific rare CNVs between autism and schizophrenia. By combining our data with prior CNV studies of schizophrenia and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7,545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with schizophrenia (p = 0.02) and an odds ratio estimate of 17 (95% CI: 1.36–1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior schizophrenia family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for schizophrenia susceptibility. Copy Number alanysis was performed on 245 cases and 490 controls of Ashkenazi Jewish descent. Samples were analyzed for deletions greater than 500 kb, with 20 or more snps in the interval. Three algorithms were used for analysis, GADA, GLAD and BEAST. The reference was created by using all samples processed here as the reference.
2010-08-06 | E-GEOD-23201 | biostudies-arrayexpress
Project description:Genetic analyses of psychiatric illnesses, such as bipolar disorder (BPD), have revealed essential information regarding the underlying pathological mechanisms. While such studies in populations of European ancestry have achieved prominent success, understanding the genetic risk factors of these illnesses (especially BPD) in Chinese population remains an urgent task. Given the lack of genome-wide association study (GWAS) of BPD in Chinese population from Mainland China, replicating the previously reported GWAS hits in distinct populations will provide valuable information for future GWAS analysis in Han Chinese. In the present study, we have recruited 1146 BPD cases and 1956 controls from Mainland China for genetic analyses, as well as 65 Han Chinese brain amygdala tissues for mRNA expression analyses. Using this clinical sample, one of the largest Han Chinese BPD samples till now, we have conducted replication analyses of 21 single nucleotide polymorphisms (SNPs) extracted from previous GWAS of distinct populations. Among the 21 tested SNPs, 16 showed the same direction of allelic effects in our samples compared with previous studies; 6 SNPs achieved nominal significance (p < 0.05) at one-tailed test, and 2 additional SNPs showed marginal significance (p < 0.10). Aside from replicating previously reported BPD risk SNPs, we herein also report several intriguing findings: (1) the SNP rs174576 was associated with BPD in our Chinese sample and in the overall global meta-analysis, and was significantly correlated with FADS1 mRNA in diverse public RNA-seq datasets as well as our in house collected Chinese amygdala samples; (2) two (partially) independent SNPs in MAD1L1 were both significantly associated with BPD in our Chinese sample, which was also supported by haplotype analysis; (3) a rare SNP rs78089757 in 10q26.13 region was a genome-wide significant variant for BPD in East Asians, and this SNP was near monomorphic in Europeans. In sum, these results confirmed several significant BPD risk genes. We hope this Chinese BPD case-control sample and the current brain amygdala tissues (with continuous increasing sample size in the near future) will provide helpful resources in elucidating the genetic and molecular basis of BPD in this major world population.
| S-EPMC6286364 | biostudies-literature
Project description:Bipolar disorder (BD) is a complex psychiatric disorder with strong heritability. Identification of new BD risk genes will help determine the mechanism underlying disease pathogenesis. In the present study, we carried out whole genome sequencing for a Chinese BD family with three affected members and three unaffected members, and identified multiple candidate causal variations, including a frameshift mutation in the GOLGB1 gene. Since a GOLGB1 missense mutation was also found in another BD pedigree, we carried out functional studies by downregulating Golgb1 expression in the brain of neonatal mice. Golgb1 deficiency had no effect on anxiety, memory, and social behaviors in young adult mice. However, we found that young adult mice with Golgb1 deficiency exhibited elevated locomotor activity and decreased depressive behaviors in the tail suspension test and the sucrose preference test, but increased depressive behaviors in the forced swim test, resembling the dual character of BD patients with both mania and depression. Moreover, Golgb1 downregulation reduced PSD93 levels and Akt phosphorylation in the brain. Together, our results indicate that GOLGB1 is a strong BD risk gene candidate whose deficiency may result in BD phenotypes possibly through affecting PSD93 and PI3K/Akt signaling.
| S-EPMC9482626 | biostudies-literature
Project description:Independent genome-wide association studies have implicated a common single nucleotide polymorphism within the ANK3 gene (rs10994336) in bipolar disorder (BD) susceptibility, thus establishing rs10994336 marker as a strong candidate predisposing genetic factor for BD. Furthermore, recent findings demonstrate that this variant impacts on cognitive functioning in BD patients, their unaffected relatives, and healthy controls by influencing sustained attention. Here, we aimed to replicate this finding in a large population-based sample of healthy young adults (n=1808). Sustained attention was evaluated using the Continuous Performance Test as in the original study and working memory was assessed with the n-back task. Individuals carrying the BD risk T-allele showed significantly reduced sensitivity in target detection, increased errors of commission, and atypical response latency variability. In addition, we confirmed the lack of an association between the rs10994336 variant and working memory, as well as general intellectual ability, suggesting a specific effect on the Continuous Performance Test performance.
| S-EPMC5744587 | biostudies-literature
Project description:The D-amino acid oxidase activator (DAOA, previously known as G72) gene, mapped on 13q33, has been reported to be genetically associated with bipolar disorder (BP) in several populations. The consistency of associated variants is unclear and rare variants in exons of the DAOA gene have not been investigated in psychiatric diseases. We employed a conditional linkage method-STatistical Explanation for Positional Cloning (STEPC) to evaluate whether any associated single nucleotide polymorphisms (SNPs) account for the evidence of linkage in a pedigree series that previously has been linked to marker D13S779 at 13q33. We also performed an association study in a sample of 376 Caucasian BP parent-proband trios by genotyping 38 common SNPs in the gene region. Besides, we resequenced coding regions and flanking intronic sequences of DAOA in 555 Caucasian unrelated BP patients and 564 mentally healthy controls, to identify putative functional rare variants that may contribute to disease. One SNP rs1935058 could "explain" the linkage signal in the family sample set (P = 0.055) using STEPC analysis. No significant allelic association was detected in an association study by genotyping 38 common SNPs in 376 Caucasian BP trios. Resequencing identified 53 SNPs, of which 46 were novel SNPs. There was no significant excess of rare variants in cases relative to controls. Our results suggest that DAOA does not have a major effect on BP susceptibility. However, DAOA may contribute to bipolar susceptibility in some specific families as evidenced by the STEPC analysis.
| S-EPMC2753761 | biostudies-literature