The impact of CACNA1C gene,and its epistasis with ZNF804A,on white matter microstructure in health,schizophrenia and bipolar disorder1

Genome‐wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium‐channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract‐based spatial statistics and threshold‐free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ‐specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.     

CACNA1C Risk Variant and Amygdala Activity in Bipolar Disorder,Schizophrenia and Healthy Controls

Objectives

Several genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups.

Methods

Rs1006737 was genotyped in 250 individuals (N = 66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group.

Results

In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups.

Conclusions

These results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ.     

Bipolar disorder risk alleles in adult ADHD patients

Attention-deficit/hyperactivity disorder (ADHD) has an estimated prevalence of 3-5% in adults. Genome-wide association (GWA) studies have not been performed in adults with ADHD and studies in children have so far been inconclusive, possibly because of the small sample sizes. Larger GWA studies have been performed on bipolar disorder (BD) and BD symptoms, and several potential risk genes have been reported. ADHD and BD share many clinical features and comorbidity between these two disorders is common. We therefore wanted to examine whether the reported BD genetic variants in CACNA1C, ANK3, MYO5B, TSPAN8 and ZNF804A loci are associated with ADHD or with scores on the Mood Disorder Questionnaire (MDQ), a commonly used screening instrument for bipolar spectrum disorders. We studied 561 adult Norwegian ADHD patients and 711 controls from the general population. No significant associations or trends were found between any of the single nucleotide polymorphisms (SNPs) studied and ADHD [odds ratios (ORs) ≤ 1.05]. However, a weak association was found between rs1344706 in ZNF804A (OR = 1.25; P = 0.05) and MDQ. In conclusion, it seems unlikely that these six SNPs with strong evidence of association in BD GWA studies are shared risk variants between ADHD and BD.     

Genetics of psychosis; insights from views across the genome

The major psychotic illnesses, schizophrenia and bipolar disorder (BD), are among the most heritable common disorders, but finding specific susceptibility genes for them has not been straightforward. The reasons are widely assumed to include lack of valid phenotypic definition, absence of good theories of pathophysiology for candidate gene studies, and the involvement of many genes, each making small contributions to population risk. Within the last year or so, a number of genome wide association (GWAS) of schizophrenia and BD have been published. These have produced stronger evidence for association to specific risk loci than have earlier studies, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in bipolar disorder. The ZNF804A and CACNA1C loci appear to influence risk for both disorders, a finding that supports the hypothesis that schizophrenia and BD are not aetiologically distinct. In the case of schizophrenia, a number of rare copy number variants have also been detected that have fairly large effect sizes on disease risk, and that additionally influence risk of autism, mental retardation, and other neurodevelopmental disorders. The existing findings point to some likely pathophysiological mechanisms but also challenge current concepts of disease classification. They also provide grounds for optimism that larger studies will reveal more about the origins of these disorders, although currently, very little of the genetic risk of either disorder is explained.     

Influence of CTNNB1 rs2953 polymorphism on schizophrenia susceptibility in Chinese Han population through modifying miR‐485 binding to CTNNB1

Schizophrenia (SCZ) and bipolar disorder (BD) are two major neuropsychiatric diseases that are the most substantial causes of disability and mortality worldwide. CTNNB1 encodes beta‐catenin, an important protein in canonical Wnt signaling. We aimed to investigate the association between the rs2953 of CTNNB1 and the risk of SCZ and BD and to further explore the function of rs2953. A total of 1658 samples (548 SCZ cases, 512 BD cases, and 598 controls) were examined in terms of the genotype of CTNNB1 rs2953. The mRNA expression level of CTNNB1 significantly increased in the SCZ and BD groups compared with that in the control group. Significant association remained between CTNNB1 3′‐untranslated region (UTR) variant rs2953 and SCZ susceptibility (additive and dominant model) after gender and age were adjusted. rs2953 disrupted the binding of CTNNB1 and miR‐485. miR‐485 significantly suppressed the luciferase activity of CTNNB1‐T vector by binding to the CTNNB1 3′‐UTR containing the T allele of rs2953. The mRNA expression of CTNNB1 can be used as a biomarker for the diagnosis of SCZ and BD. The 3′‐UTR variant rs2953 in CTNNB1 influences the risk of SCZ in the Han Chinese population and modifies the binding of miR‐485 to CTNNB1.     

Association Between rs1344706 of ZNF804A and Schizophrenia:A Meta-analysis

Schizophrenia is one of the most serious mental diseases found in humans. Previous studies indicated that the single nucleotide polymorphism（SNP） rs1344706 in the gene ZNF804 A encoding zinc finger protein 804 A was associated with schizophrenia in Caucasian population but not in Chinese Han population. However, current results are conflicting in Asian population. In the present study, a meta-analysis was performed to revisit the association between rs1344706 and the risk of schizophrenia in Asian, Caucasian and other populations. Electronic search of Pub Med database identified 25 case–control studies with available genotype frequencies of rs1344706 for the meta-analysis,involving a total of 15,788 cases and 22,654 controls. A pooled odds ratio（OR） with 95% confidence interval（CI） was used to assess the association. The current meta-analysis showed an association between rs1344706 and schizophrenia in Caucasian populations（P = 0.028, OR = 1.138, 95% CI：1.014–1.278; P = 0.004 for heterogeneity） and Asian populations（P = 0.008, OR = 1.092, 95%CI： 1.023–1.165; P = 0.001 for heterogeneity）, but not in other populations（P = 0.286,OR = 1.209, 95% CI： 0.853–1.714, P = 0.120 for heterogeneity）. Egger’s test（P 〉 0.05） and Begg’s test（P 〉 0.05） are both suggestive of the lack of publication bias for the included studies. Thus, the absence of association in other populations suggests a genetic heterogeneity in the susceptibility of schizophrenia and demonstrates the difficulties in replicating genome-wide association study findings regarding schizophrenia across different ethnic populations. To validate the association between rs1344706 and schizophrenia, further studies with larger participant populations worldwide are needed.     

Meta-Analysis Indicates That the European GWAS-Identified Risk SNP rs1344706 within ZNF804A Is Not Associated with Schizophrenia in Han Chinese Population

Recent genetic association studies have implicated several candidate susceptibility variants for schizophrenia among general populations. Rs1344706, an intronic SNP within ZNF804A, was identified as one of the most compelling candidate risk SNPs for schizophrenia in Europeans through genome-wide association studies (GWASs) and replications as well as large-scale meta-analyses. However, in Han Chinese, the results for rs1344706 are inconsistent, and whether rs1344706 is an authentic risk SNP for schizophrenia in Han Chinese is inconclusive. Here, we conducted a systematic meta-analysis of rs1344706 with schizophrenia in Chinese population by combining all available case-control samples (N = 12), including a total of 8,982 cases and 12,342 controls. The results of our meta-analysis were not able to confirm an association of rs1344706 A-allele with schizophrenia (p = 0.10, odds ratio = 1.06, 95% confidence interval = 0.99–1.13). Such absence of association was further confirmed by the non-superiority test (p = 0.0003), suggesting that rs1344706 is not a risk SNP for schizophrenia in Han Chinese. Detailed examinations of individual samples revealed potential sampling bias in previous replication studies in Han Chinese. The absence of rs1344706 association in Han Chinese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating genome-wide association findings of schizophrenia across different ethnic populations.     

Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population

AimsAlthough polymorphisms in IL23R have recently been proposed to predispose to Behcet's disease (BD), associations between IL23R polymorphisms and intestinal BD have yet to be elucidated. We therefore performed a study to evaluate whether IL17A, IL23R, and STAT4 polymorphisms are associated with susceptibility to intestinal BD in the Korean population.Main methodsSingle nucleotide polymorphisms (SNP) in the IL17A, IL23R, and STAT4 genes were analyzed using DNA sequencing, denaturing high performance liquid chromatography, and TaqMan genotyping assays.Key findingsIndividual polymorphism analysis revealed that the TT genotype of IL17A rs8193036 (odds ratio (OR) 2.10, 95% confidence interval (CI) (1.12–3.92), p = 0.021), and GG + GT genotype of IL23R rs1884444 (OR 1.92, 95% CI (1.03–3.57), p = 0.034) was associated with the development of intestinal BD. When these two genotypes were combined, the risk of BD increased compared to that of patients with no-risk or one-risk genotype (OR 2.21, 95% CI (1.13–4.34), p = 0.021). Furthermore, statistically significant gene–gene interactions were observed between G149R in IL23R vs. rs11685878 in STAT4, rs2275913 in IL17A vs. rs7574865 in STAT4, and rs11889341 in STAT4 vs. rs2275913 in IL17A. The haplotypes of IL17A had a positive association with intestinal BD risks, whereas those of IL23R were protective for disease development.SignificanceOur results indicate that the interaction of specific IL17A, IL23R, and STAT4 SNPs modulate susceptibility to intestinal BD in the Korean population, suggesting that the IL-17/23 axis plays a significant role in disease pathogenesis.     

Association between single nucleotide polymorphisms of TPH1 and TPH2 genes,and depressive disorders

Tryptophan catabolites pathway disorders are observed in patients with depression. Moreover, single nucleotide polymorphisms of tryptophan hydroxylase genes may modulate the risk of depression occurrence. The objective of our study was to confirm the association between the presence of polymorphic variants of TPH1 and TPH2 genes, and the development of depressive disorders. Six polymorphisms were selected: c.804‐7C>A (rs10488682), c.‐1668T>A (rs623580), c.803+221C>A (rs1800532), c.‐173A>T (rs1799913)—TPH1, c.‐1449C>A (rs7963803), and c.‐844G>T (rs4570625)—TPH2. A total of 510 DNA samples (230 controls and 280 patients) were genotyped using TaqMan probes. Among the studied polymoorphisms, the G/G genotype and G allele of c.804‐7C>A—TPH1, the T/T homozygote of c.803+221C>A—TPH1, the A/A genotype and A allele of c.1668T>A—TPH1, the G/G homozygote and G allele of c.‐844G>T—TPH2, and the C/A heterozygote and A allele of c.‐1449C>A—TPH2 were associated with the occurrence of depression. However, the T/T homozygote of c.‐1668T>A—TPH1, the G/T heterozygote and T allele of c.‐844G>T—TPH2, and the C/C homozygote and C allele of c.‐1449C>A—TPH2 decreased the risk of development of depressive disorders . Each of the studied polymorphisms modulated the risk of depression for selected genotypes and alleles. These results support the hypothesis regarding the involvement of the pathway in the pathogenesis of depression.     

Association of the variants in the BUD13‐ZNF259 genes and the risk of hyperlipidaemia

The single nucleotide polymorphisms (SNPs) in the BUD13 homolog (BUD13) and zinc finger protein 259 (ZNF259) genes have been associated with one or more serum lipid traits in the European populations. However, little is known about such association in the Chinese populations. Our objectives were to determine the association of the BUD13/ZNF259 SNPs and their haplotypes with hypercholesterolaemia (HCH)/hypertriglyceridaemia (HTG) and to identify the possible gene–gene interactions among these SNPs. Genotyping of 6 SNPs was performed in 634 hyperlipidaemic and 547 normolipidaemic participants. The ZNF259 rs2075290, ZNF259 rs964184 and BUD13 rs10790162 SNPs were significantly associated with serum lipid levels in both HCH and non‐HCH populations (P < 0.008–0.001). On single locus analysis, only BUD13 rs10790162 was associated with HCH (OR: 2.23, 95% CI: 1.05, 4.75, P = 0.015). The G‐G‐A‐A‐C‐C haplotype, carrying rs964184‐G‐allele, was associated with increased risk of HCH (OR: 1.35, 95% CI: 1.10, 1.66, P = 0.005) and HTG (OR: 1.75, 95% CI: 1.39, 2.21, P = 0.000). The A‐C‐G‐G‐C‐C and A‐C‐A‐G‐T‐C haplotypes, carrying rs964184‐C‐allele, were associated with reduced risk of HCH (OR: 0.77, 95% CI: 0.61, 0.99, P = 0.039 and OR: 0.66, 95% CI: 0.47, 0.94, P = 0.021 respectively). On multifactor dimensionality reduction analyses, the two‐ to three‐locus models showed a significant association with HCH and HTG (P < 0.01–0.001). The BUD13/ZNF259 SNPs, which were significant in the European populations, are also replicable in the Southern Chinese population. Moreover, inter‐locus interactions may exist among these SNPs. However, further functional studies are required to clarify how these SNPs and genes actually affect the serum lipid levels.     

Association between two single nucleotide polymorphisms at corresponding microRNA and schizophrenia in a Chinese population

Numerous linkage and association studies have been performed to identify genetic predispositions to schizophrenic (SCZ) in different populations, but its genetic basis remains unclear. Some findings may provide a clue in understanding the association between abnormal immunity and SCZ. MicroRNA (miRNA) involves in regulating both schizophrenic and immunity as previous reported. And single nucleotide polymorphisms (SNPs) within miRNAs can change their characteristics, resulting in functional and/or phenotypic changes. So two SNPs (hsa-pre-mir-146a rs2910164 G>C and hsa-mir-499 rs3746444 T>C) at two miRNAs, were genotyped to demonstrate their association with susceptibility to SCZ. Polymorphisms were analyzed among 268 Chinese schizophrenic patients and 232 healthy controls by PCR-RFLP and validated by sequencing. No association was found between the two polymorphisms and SCZ either in cases or in controls. SCZ patients with family history showed significant increase of the G allele frequency of rs2910164 in comparison to those without (P = 0.018). The CC genotype frequency of rs3746444 was also higher in the patients having hallucinations than those without hallucinations (P = 0.012). In addition, patients carrying CC genotype of rs3746444 were more likely to be lack of motivation in comparison to normal controls (P = 0.042). Allele and genotype frequency of rs2910164 showed no significant difference between patients and normal subjects or between patients with and without clinical variables. Although patients carrying CC genotype of rs3746444 were found to be more likely to develop hallucination and individuals carrying C allele to lack motivation, there is lacking association between SCZ and the two SNPs at miRNAs, which may regulate immune response.     

Association of SLC18A1, TPH1, and RELN gene polymorphisms with risk of paranoid schizophrenia

A biochip was developed to examine the polymorphisms of genes associated with schizophrenia risk, including DISC1, RELN, ZNF804A, PLXNA2, COMT, SLC18A1, CACNA1C, ANK2, TPH1, PLAA, and SNAP-25. Allele and genotype frequencies of the genes were determined in 198 schizophrenics and 192 healthy subjects from Bashkortostan (ethnic Russians and Tatars). The frequencies of allele A (p = 0.007) and genotype AA (p = 0.002) of the rs2270641 A>C polymorphism of SLC18A1 in the patients with paranoid schizophrenia was lower than in the healthy subjects. The frequency of genotype AA of the rs1800532 C>A polymorphism of TPH1 in the schizophrenics was higher than in the healthy subjects (p = 0.036). Compared with the healthy subjects, the ethnic Tatar patients with paranoid schizophrenia had a lower frequency of allele C of the rs7341475 C>T polymorphism of RELN (p = 0.039) and a higher frequency of genotype AA of the rs1800532 C>A polymorphism of TPH1 (p = 0.019, OR = 2.52, CI 1.18-5.38). The frequency of allele C (p = 0.0001) and genotype GC (p = 0.0001) of the rs1327175 G>C polymorphism of PLXNA2 was elevated in the patients with a family history of paranoid schizophrenia. Based on the results, the SLC18A1, TPH1, and RELN polymorphisms were associated with risk of schizophrenia.     

A gene's eye view of epistasis,selection and speciation

In this mini‐review, I discuss the effects of gene interaction or epistasis from a `gene's eye view.' By a `gene's eye view' of epistasis, I mean that I will consider a single, bi‐allelic locus, A , whose effects on fitness result only from its interactions with alleles of another, unknown locus, X . I will show how changes in the frequencies of alleles at the background locus affect the relationship of alleles at the A ‐locus to fitness. Changing the genetic background changes the fundamental characteristics of the A ‐locus, such as the magnitude and sign of allelic effects on fitness, and, consequently, it changes the strength and pattern of selection. I consider each of the four kinds of pair–wise interactions between two loci and show that some kinds of epistasis are more sensitive than others to population genetic subdivision. Lastly, I show that some kinds of epistasis are more likely than others to affect the process of speciation and contribute to or be responsible for general genetic features of interspecific hybrids, such as Haldane's rule.     

Association between circadian genes,bipolar disorders and chronotypes

Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR?=?1.49 95%CI[1.18–1.88]; p?=?0.0008) and rs782931 in RORA (OR?=?1.31 95%CI[1.12–1.54]; p?=?0.0006) and BD. Then we used a “reverse phenotyping approach” to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p?=?0.04) and languid circadian type (p?=?0.01), whereas rs782931 was associated with rigid circadian type (p?=?0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.     

BDNF genotype is associated with hippocampal volume in mild traumatic brain injury

The negative long‐term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative‐type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain‐derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single‐nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non‐Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.