<Emphasis Type="Italic">ADCY5</Emphasis>-related dyskinesia presenting as familial myoclonus-dystonia

We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated with a novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse whole-exome sequencing data from an affected grandmother-granddaughter pair. Whole-exome sequencing identified 18,000 shared variants, of which 46 were non-synonymous changes not present in a local cohort of control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele frequency in the 1000 Genomes Project and on phylogenetic conservation yielded 13 candidate variants, of which the heterozygous missense mutation c.3086T>G, p. M1029R in ADCY5 most closely matched the observed phenotype. This report illustrates the utility of whole-exome sequencing in cases of undiagnosed movement disorders with clear autosomal dominant inheritance. Moreover, ADCY5 mutations should be considered in cases with apparent myoclonus-dystonia, particularly where SCGE mutations have been excluded. ADCY5-related dyskinesia may manifest variable expressivity within a single family, and affected individuals may be initially diagnosed with differing neurological phenotypes.     

No association found between the promoter variations of QKI and schizophrenia in the Chinese population

BackgroundSchizophrenia is a chronic psychiatric disorder with a strong genetic component. Several recent published studies have reported that the mRNA expression level of quaking homolog, KH domain RNA binding (QKI) is down regulated in individuals diagnosed with schizophrenia.MethodsWe were interested in the genetic variants around the promoter region of QKI and selected seven variants in this region, namely rs4263561, rs3904720, rs387504, rs3763197, rs7772756, rs7758706 and rs4709716. For the study we recruited 288 individuals diagnosed with schizophrenia and 288 control subjects. All the recruits were from Shanghai and were Han Chinese in origin.ResultsNo individual SNP nor any haplotype was found to be associated with schizophrenia.ConclusionsThese results suggest that the variants within the promoter region of QKI gene are unlikely to play a major role in susceptibility to schizophrenia in the Chinese population.     

Rare variants in LRRK1 and Parkinson's disease

Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow-up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.     

Investigation of tryptophan hydroxylase 2 (TPH2) in schizophrenia and in the response to antipsychotics

Serotonergic transmission is considered relevant in the pathophysiology and the treatment of schizophrenia. Tryptophan hydroxylase (TPH) is the rate limiting enzyme in the biosynthesis of serotonin. While the TPH1 gene has been found to be associated with schizophrenia, studies focusing on TPH2 variants did not yield conclusive results for schizophrenia or the response to antipsychotic medication. We analyzed eleven TPH2 SNPs in two case–control samples consisting of 4453 individuals in total. Six SNPs were selected because of their potential functional relevance (rs4570625, rs11178997, rs11178998, rs7954758, rs7305115, and, rs4290270) and were supported by another 5 tagging SNPs selected based on HapMap LD information. In the discovery sample (1476 individuals), we observed a significant association with schizophrenia for rs10784941 (p = 0.009, OR minor G-allele 0.82 [0.71–0.95]) and rs4565946 (p = 0.011, OR minor T-allele 0.83 [0.71–0.96]). Association was also observed with a common rs4570625–rs4565946 haplotype (OR G-C haplotype 1.20 [1.02–1.40]; p = 0.0046). Single-marker associations could not be replicated in the replication sample consisting of 2977 individuals, but there was a strong trend regarding the rs4570625–rs4565946 G-C haplotype (OR 1.10 [0.98–1.24]; p(one-sided test) = 0.054). In smaller sub-samples, the rare rs4570625–rs4565946 T-T haplotype was associated with reduced processing speed (n = 193, p = 0.004) and sensorimotor gating (n = 68, p = 0.006) of schizophrenia patients. TPH2 variants and the rs4570625–rs4565946 G-C haplotype did not influence the beneficial response to antipsychotic drugs (n = 210) after four weeks of treatment administering the Positive and Negative Syndrome Scale of Schizophrenia (PANSS). We also investigated the association of the SNPs to treatment response, but did not get significant results. In sum, our results argue for only a minor role of TPH2 in schizophrenia.     

Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response

GDNF (glial-cell-line derived neurotrophic factor) is a potent neurotrophic factor for dopaminergic neurons. Neuropsychiatric diseases and their treatments are associated with alterations in the levels of both GDNF and its receptor family (GDNF family receptor alpha or GFRA). GFRA1, GFRA2 and GFRA3 are located in chromosomal regions with suggestive linkage to schizophrenia. In this study we analyzed polymorphisms located in all four known GFRA genes and examined association with schizophrenia and clozapine response. We examined SNPs across the genes GFRA1-4 in 219 matched case-control subjects, 85 small nuclear families and 140 schizophrenia patients taking clozapine for 6 months. We observed that GFRA3 rs11242417 and GFRA1 rs11197557 variants were significantly associated with schizophrenia after combining results from both schizophrenia samples. Furthermore, we found an overtransmission of the G-C GFRA1 rs7920934-rs730357 haplotype to subjects with schizophrenia and association of A-T-G-G GFRA3 rs10036665-rs10952-rs11242417-rs7726580 with schizophrenia in the case-control sample. On the other hand, GFRA2 variants were not associated with schizophrenia diagnosis but subjects carrying T-G-G rs1128397-rs13250096-rs4567028 haplotype were more likely to respond to clozapine treatment. The statistical significance of results survived permutation testing but not Bonferroni correction. We also found nominally-significant evidence for interactions between GFRA1, 2 and 3 associated with schizophrenia and clozapine response, consistent with the locations of these three genes within linkage regions for schizophrenia.     

Association of Single-Nucleotide Polymorphisms in the Cannabinoid Receptor 2 Gene with Schizophrenia in the Han Chinese Population

Cannabinoid receptor 2 (CNR2) is a major receptor in the endogenous cannabinoid system. In recent years, many studies have shown that the receptor is closely associated with schizophrenia. This study examined the relationship between CNR2 gene polymorphisms (rs2501432C/T, rs2229579C/T, rs2501401G/A) and schizophrenia. Three hundred sixteen schizophrenia patients and 334 healthy subjects were recruited as case and control groups, respectively. For rs2501432, the CT/TT genotype frequencies in the dominant model, TT genotype frequencies in the additive model, and T allele frequencies of the case group were lower than the control (P?<?0.05), and the CT and TT genotypes and T allele frequencies of the male case group were significantly lower than the control (P?<?0.05). For rs2229579, the T allele frequencies of the case group were higher than the control (P?<?0.05). The T-C-G haplotype in the case group had a significantly lower frequency compared with the controls, but the T-T-A haplotype frequencies were higher in the case group than in the controls (P?<?0.05). Our results suggest that the T allele of rs2501432 may be a protective factor, particularly in males, but the T allele of rs2229579 may be a risk factor for schizophrenia. T-C-G may be a protective haplotype for schizophrenia, but not the T-T-A haplotype.     

A Swedish family with de novo α-synuclein A53T mutation: Evidence for early cortical dysfunction

A de novo α-synuclein A53T (p.Ala53 Th; c.209G > A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria, and cognitive decline. Longitudinal clinical follow-up, EEG, SPECT and CSF biomarker examinations suggested an underlying encephalopathy with cortical involvement. The mutated allele (c.209A) was present within a haplotype different from that shared among mutation carriers in the Italian (Contursi) and the Greek-American Family H kindreds. One unaffected family member carried the mutation haplotype without the c.209A mutation, strongly suggesting its de novo occurrence within this family. Furthermore, a novel mutation c.488G > A (p.Arg163His; R163H) in the presenilin-2 (PSEN2) gene was detected, but was not associated with disease state.     

Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A

PurposeTo describe the spectrum of clinical disease in a mutliplex family with an autosomal dominant form of generalized epilepsy with febrile seizures plus (GEFS+) and determine its genetic etiology.MethodsMedical and family history was obtained on 11 clinically affected individuals and their relatives across three generations through medical chart review and home visits. A candidate gene approach including haplotype analysis and direct sequencing was used.ResultsAn epilepsy-associated haplotype was identified on 2q24. Direct sequencing of the entire SCN1A gene identified seven sequence variants. However, only one of these, c.1162 T > C, was not found in population controls. This transition in exon 8 of SCN1A predicts a substitution (Y388H) of a highly conserved tyrosine residue in the loop between transmembrane segments S5 and S6 of the sodium channel protein (Na_v1.1). Clinical features in mutation carriers of this novel missense mutation were highly variable, ranging from febrile seizures to severe refractory epilepsy.ConclusionA novel missense mutation in the pore-forming region of the sodium channel gene SCN1A causes GEFS+ with a variable phenotype that includes mood and anxiety disorders, as well as ataxia, expanding the GEFS+ spectrum to include neuropsychiatric disease.     

Systematic Integration of Brain eQTL and GWAS Identifies ZNF323 as a Novel Schizophrenia Risk Gene and Suggests Recent Positive Selection Based on Compensatory Advantage on Pulmonary Function

Genome-wide association studies have identified multiple risk variants and loci that show robust association with schizophrenia. Nevertheless, it remains unclear how these variants confer risk to schizophrenia. In addition, the driving force that maintains the schizophrenia risk variants in human gene pool is poorly understood. To investigate whether expression-associated genetic variants contribute to schizophrenia susceptibility, we systematically integrated brain expression quantitative trait loci and genome-wide association data of schizophrenia using Sherlock, a Bayesian statistical framework. Our analyses identified ZNF323 as a schizophrenia risk gene (P = 2.22×10^–6). Subsequent analyses confirmed the association of the ZNF323 and its expression-associated single nucleotide polymorphism rs1150711 in independent samples (gene-expression: P = 1.40×10^–6; single-marker meta-analysis in the combined discovery and replication sample comprising 44123 individuals: P = 6.85×10⁻¹⁰). We found that the ZNF323 was significantly downregulated in hippocampus and frontal cortex of schizophrenia patients (P = .0038 and P = .0233, respectively). Evidence for pleiotropic effects was detected (association of rs1150711 with lung function and gene expression of ZNF323 in lung: P = 6.62×10^–5 and P = 9.00×10^–5, respectively) with the risk allele (T allele) for schizophrenia acting as protective allele for lung function. Subsequent population genetics analyses suggest that the risk allele (T) of rs1150711 might have undergone recent positive selection in human population. Our findings suggest that the ZNF323 is a schizophrenia susceptibility gene whose expression may influence schizophrenia risk. Our study also illustrates a possible mechanism for maintaining schizophrenia risk variants in the human gene pool.Key words: schizophrenia, ZNF323, association, eQTL, hippocampus, positive selection     

The interleukin 10 promoter haplotype ACA and the long-form variant of the DRD4 uVNTR polymorphism are associated with vulnerability to schizophrenia

A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin-10 (IL-10) promoter and DRD4 uVNTR polymorphisms. DRD4 long-form variants (namely, those with ≥ 5 repeats), homozygosity for the 4-repeat allele, and the IL-10 haplotype ACA were associated with schizophrenia, respectively. No obvious interactions among the potential polymorphisms were found, which suggests that IL-10 and DRD4 confer vulnerability to schizophrenia independently.     

DAOA/G72 predicts the progression of prodromal syndromes to first episode psychosis

The genetic factors determining the progression of prodromal syndromes to first episode schizophrenia have remained enigmatic to date. In a unique prospective multicentre trial, we assessed whether variants at the d-amino acid oxidase activator (DAOA)/G72 locus influence progression to psychosis. Young subjects with a prodromal syndrome were observed prospectively for up to 2 years to assess the incidence of progression to schizophrenia or first episode psychosis. Of the 82 probands with a prodromal syndrome, 21 probands experienced progression to psychosis within the observation period. Assessment of nine common variants in the DAOA/G72 locus yielded two variants with the predictive value for symptom progression: all four probands with the rs1341402 CC genotype developed psychosis compared with 17 out of 78 probands with the TT or CT genotypes (χ² = 12.348; df = 2; p = 0.002). The relative risk for progression to psychosis was significantly increased in the CC genotype: RR = 4.588 (95% CI = 2.175–4.588). Similarly, for rs778294, 50% of probands with the AA genotype, but only 22% of probands with a GG or GA genotype progressed to psychosis (χ² = 7.027; df = 2; p = 0.030). Moreover, haplotype analysis revealed a susceptibility haplotype for progression to psychosis. This is one of the first studies to identify a specific genetic factor for the progression of prodromal syndromes to schizophrenia, and further underscores the importance of the DAOA/G72 gene for schizophrenia.     

Lack of association between HTR4 gene polymorphisms and schizophrenia in case–control and family-based samples

Previous studies have found haplotypic association of HTR4 variants and schizophrenia. Examining case–control pairs, G–G of rs7713886 was associated with schizophrenia risk. The A–A–G–G–G–A–A rs9325104-rs1422636-rs7715569-rs6873382-rs7711800-rs10078551-rs2068190 haplotype was overrepresented in the schizophrenia cases. The associations were no longer significant after corrections for multiple comparisons. No association was found in the family sample.     

Genetic association of cyclic AMP signaling genes with bipolar disorder

The genetic basis for bipolar disorder (BPD) is complex with the involvement of multiple genes. As it is well established that cyclic adenosine monophosphate (cAMP) signaling regulates behavior, we tested variants in 29 genes that encode components of this signaling pathway for associations with BPD type I (BPD I) and BPD type II (BPD II). A total of 1172 individuals with BPD I, 516 individuals with BPD II and 1728 controls were analyzed. Single SNP (single-nucleotide polymorphism), haplotype and SNP × SNP interactions were examined for association with BPD. Several statistically significant single-SNP associations were observed between BPD I and variants in the PDE10A gene and between BPD II and variants in the DISC1 and GNAS genes. Haplotype analysis supported the conclusion that variation in these genes is associated with BPD. We followed-up PDE10A''s association with BPD I by sequencing a 23-kb region in 30 subjects homozygous for seven minor allele risk SNPs and discovered eight additional rare variants (minor allele frequency <1%). These single-nucleotide variants were genotyped in 999 BPD cases and 801 controls. We obtained a significant association for these variants in the combined sample using multiple methods for rare variant analysis. After using newly developed methods to account for potential bias from sequencing BPD cases only, the results remained significant. In addition, SNP × SNP interaction studies suggested that variants in several cAMP signaling pathway genes interact to increase the risk of BPD. This report is among the first to use multiple rare variant analysis methods following common tagSNPs associations with BPD.     

The lack of association between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms and schizophrenia in a group of Turkish population

IntroductionSchizophrenia is a complex neuropsychiatric disorder with deficits of multiple domains of cognitive functions, volition and emotions. Family and twin studies have provided cumulative evidence for the genetic basis of schizophrenia. The aetiolgy of this disease involves the interplay of multifactiorial inheritance operating on brain maturational processes and polygenic inheritance with some genes showing susceptibility at many genomic locations such as 22q and 11q.The catechol-O-methyltransferase (COMT-22q11) is an extensively studied candidate gene for schizophrenia. COMT acts as an enzymatic detoxicating barrier between the blood and other tissues regulating the amounts of active dopamine and norepinephrine in various parts of the brain and therefore to be associated with schizophrenia.The presence of a common functional single nucleotide polymorphism (SNP) in exon 4 [Guanine (G) Adenine (A); Val108/158Met], alters the enzymatic activity with a trimodal distribution of high-HH, intermediate-HL and low-LL activity alleles which appear to have association with schizophrenia.Brain-derived neurotrophic factor (BDNF-11q13) is a member of the nerve growth factor family working as a molecular regulator of neuronal development and plasticity. Molecules that are critical in the development and survival of neurons such as BDNF play a significant role in the neuropathology of schizophrenia. While upregulation of BDNF increases the neuronal cell size and synaptic plasticity, a functional polymorphism at codon 66 [G→A; Val66Met] down regulates this process and induces schizophrenia.ObjectiveIn the present study, our aim was to investigate the differences in allele frequencies between schizophrenic patients [n = 97 (51 men, 46 women)] and control group [n = 376 (228 men, 148 women)] subjects.ResultsWhen the control and schizophrenia groups were compared for BDNFVal66Met polymorphism, we did not find a significant difference between the study groups either for genotype (χ² = 3.370447, p > 0.05) or Val/Met haplotype analysis (χ² = 2.840264, p > 0.05). When a comparison was revealed for COMT-Val108/158Met polymorphism, no significant difference was detected among schizophrenia and control groups for genotype (χ² = 0.373330, p > 0.05) and Val/Met haplotype analysis (χ² = 0.339073, p > 0.05). When the control and study groups were compared for BDNFVal66Met–COMTVal108/158Met polymorphisms compound genotype and haplotype analyses, there was no significant difference between the two groups (χ² = 11.015; p > 0.05 and χ² = 3.191; p > 0.05), respectively.ConclusionOur results indicate that there is no association between schizophrenia and BDNF–COMT polymorphisms and haplotypes analysis. We also did not find an association between schizophrenia and BDNF–COMT compound genotype and haplotype analyses. Although our study is unique in Turkey as combining BDNF and COMT compound genotype–haplotype analyses, for a generalization of Turkish schizophrenia patient's susceptibility to schizophrenia; we need further studies with an enlarged cohort.     

No genetic association between NCAM1 gene polymorphisms and schizophrenia in the Chinese population

Background

The neural cell adhesion molecule 1(NCAM1, aliases NCAM and CD56) is a cell-surface molecule which makes homophilic adhesion between neural cells involved in cell migration, axon outgrowth and synaptic plasticity. Recent studies reported that NCAM1 might act as a candidate schizophrenia susceptibility gene.

Method

We genotyped five SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) within the NCAM1 gene and conducted a case-control study in 288 schizophrenic patients and 288 healthy subjects in the Chinese Han population. We compared allele and genotype frequencies and haplotype distributions between cases and controls.

Result

No significant differences in allele and genotype frequencies were found for each single SNP between schizophrenic patients and healthy subjects. Moreover, there were no significant differences in haplotype distributions between cases and controls (global χ² = 1.318, P = 0.725, df = 3).

Conclusion

Our study suggests that the five SNPs within NCAM1 gene we studied may not play a major role in the schizophrenia susceptibility in the Chinese Han population.     

Homozygosity mapping and whole exome sequencing provide exact diagnosis of Cohen syndrome in a Saudi family

BackgroundCohen syndrome (CS) is a rare multi-system autosomal recessive disorder with a high prevalence in the Finnish population. Clinical features of Finnish-type CS are homogeneous, however, in non-Finnish populations, CS diagnosis is challenging due to broad phenotypic variability.MethodsWe studied a consanguineous family having three affected individuals with clinical features of severe intellectual disability and global developmental delay. Clinical diagnosis of the phenotype could not be established based on the features. Therefore, whole genome SNP genotyping and whole exome sequencing (WES) were performed on DNA samples from affected and unaffected family members.ResultsHomozygosity mapping identified a shared loss of heterozygosity region on chromosome 8q22.1-q22.3 and WES data analysis revealed an insertion-deletion (indel) mutation (c.11519_11521delCAAinsT) in the VPS13B gene. The indel is predicted to cause a frameshift resulting in a premature termination of the VPS13B protein (NP_060360.3:p.Pro3840Leufs*2).ConclusionVPS13B encodes a giant transmembrane protein called vacuolar protein sorting 13 homolog B. VPS13B is known to play a role in the glycosylation of Golgi proteins and in endosomal-lysosomal trafficking. Moreover, it is thought to function in vesicle mediated transport and sorting of proteins within the cell. The mechanism by which abnormalities of the VPS13B protein lead to the phenotype of CS is currently unknown. Here, in this study, we successfully established a clinical diagnosis of CS cases from a family using genomic analyses. Clinical re-examination of the patients revealed characteristic ocular abnormalities.     

Common Variants in the TPH2 Promoter Confer Susceptibility to Paranoid Schizophrenia

Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. Our previous study suggested that promoter region of tryptophan hydroxylase 2 gene (TPH2) may confer the susceptibility to paranoid schizophrenia. In this study, we investigated whether common variants within TPH2 promoter may predispose to paranoid schizophrenia in Han Chinese. A total of 509 patients who met DSM-IV criteria for paranoid schizophrenia and 510 matched healthy controls were recruited for this study. Five polymorphisms within TPH2 promoter region were tested. No statistically significant differences were found in allele or genotype frequencies between schizophrenic patients and healthy controls. The frequency of the rs4448731T-rs6582071A-rs7963803A-rs4570625T-rs11178997A haplotype was significantly higher in cases compared to the controls (P?=?0.003; OR?=?1.49; 95% CI, 1.15-1.95). Our results suggest that the common variants within TPH2 promoter are associated with paranoid schizophrenia in Han Chinese. Further studies in larger samples are warranted to elucidate the role of TPH2 in the etiology of paranoid schizophrenia.     

Genetic variants of SNCA and LRRK2 genes are associated with sporadic PD susceptibility: A replication study in a Taiwanese cohort

BackgroundParkinson's disease (PD) is one of the most prevalent age-related neurodegenerative diseases and usually refers to a complex disorder with multiple genetic and environmental factors influencing disease risk. We here performed a gene-based case–control association study to scrutinize whether genetic variants in SNCA and LRRK2 genes could predispose to sporadic, late-onset form of PD in Taiwanese population.Methods17 Single Nucleotide Polymorphisms (SNPs) markers located within SNCA gene as well as the 16 SNP markers within LRRK2 gene were chosen for genotyping and evaluated their haplotype structure in a cohort of sporadic PD patients and control individuals.ResultsThis study showed that two SNPs near the promoter region (rs2301134 and rs2301135) of SNCA gene gave the greatest evidence for an association with PD (p ≤ 0.01) and a haplotype block with two SNPs in the 3′ UTR (rs356221 and rs11931074) revealed another evidence of association (p ≤ 0.02). For the LRRK2 gene, only R1628P variants of total 16 SNPs giving a marginal significant association with PD across the whole gene (p = 0.0058) and no haplotype block was constructed. Many genetic variants (A419V, I1122V, R1441C, R1441G, R1441H, Y1699C, M1869 V, M1869T, I2012T, G2019S, and I2020T) from previous reports were not detected in our cohort.ConclusionsWe have replicated a population-based PD association study in a collection of 626 cases and 473 control subjects and confirm that genetic variants of both SNCA and LRRK2 genes are associated with susceptibility to sporadic PD but in a different distribution.