DISC1 in adult ADHD patients: An association study in two European samples

The DISC1 gene was named after its discovery in a Scottish pedigree with schizophrenia (SCZ) patients. However, subsequent studies have shown association of DISC1 variants with a range of different neurocognitive phenotypes and psychiatric disorders, including bipolar disorder (BPD), and major depression. Attention‐deficit/hyperactivity disorder (ADHD) shares some symptoms with BPD and ADHD patients often suffer from comorbid affective disorders. We wanted to examine the role of DISC1 in ADHD, and with comorbid symptoms of mood disorders. Eleven single nucleotide polymorphisms (SNPs) previously implicated in SCZ and BPD, and a DISC1 duplication involving exon 1, were genotyped in 561 adult ADHD cases and 713 controls of Norwegian ancestry. The intronic SNP rs1538979 was associated with ADHD in the Norwegian sample [odds ratio (OR): 1.33, 95% confidence interval (CI) 1.03–1.73, P = 0.03] and replicated in a Spanish adult ADHD sample of 694 cases and 735 controls, using the tagging SNP rs11122330 (meta‐analysis: P = 0.008, OR 1.25, 95% CI 1.06–1.47). In the Norwegian ADHD sample we also observed an association between the Phe607‐variant of rs6675281 and a positive score on the Mood Disorder Questionnaire (MDQ; OR = 1.44, 95% CI 1.08–1.93, P = 0.01). To our knowledge, this is the first study to show an association between DISC1 variants and ADHD. Our study suggests that further studies are warranted to resolve if DISC1 variation is involved in several common neurodevelopmental disorders including ADHD. © 2013 Wiley Periodicals, Inc.     

SYNGR1 is associated with schizophrenia and bipolar disorder in southern India

Chromosome 22q11–13 is one of the most consistent linkage regions for schizophrenia (SCZ) and bipolar disorder (BPAD). The SYNGR1 gene, which is associated with presynaptic vesicles in neuronal cells, is located on 22q13.1. We have previously identified a novel nonsense mutation in the SYNGR1 gene in a SCZ pedigree. In the present study, a detailed analysis of this gene was performed in a case–control cohort (198 BPAD, 193 SCZ and 107 controls from southern India) to test for association with SCZ and BPAD. Sequence analysis of all exonic and flanking intronic regions of the SYNGR1 gene in 198 BPAD and 193 SCZ cases revealed a novel mutation Lsy99Glu (in one BPAD patient) and two other novel common polymorphisms [synonymous single nucleotide polymorphism (SNP—Ser97Ser) and an Asn ins/del] in the SYNGR1 gene. We also validated 9 out of 14 dbSNPs in our population. Case–control analysis revealed allelic (P=0.028–0.00007) association of five polymorphisms with SCZ and/or BPAD cases. Further, 3-SNP (with LD block 1 SNPs) and 2-SNP (with LD block 2 SNPs) haplotype analyses did not show any association with either SCZ or BPAD. Our results support SYNGR1 as a probable susceptibility gene for SCZ and BPAD. Also, the observed association of SYNGR1 with both SCZ and BPAD suggests the likely involvement of a common pathway in the etiology of these disorders.Electronic Supplementary Material Supplementary material is available for this article at     

Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype–phenotype correlations

Autism spectrum disorder (ASD) is a childhood neuropsychiatric disorder with a complex genetic architecture. The diagnostic potential of a targeted panel of ASD genes has only been evaluated in small cohorts to date and is especially understudied in the Chinese population. Here , we designed a capture panel with 358 genes (111 syndromic and 247 nonsyndromic) for ASD and sequenced a Chinese cohort of 539 cases evaluated with the Autism Diagnostic Interview‐Revised (ADI‐R) and the Autism Diagnostic Observation Schedule (ADOS) as well as 512 controls. ASD cases were found to carry significantly more ultra‐rare functional variants than controls. A subset of 78 syndromic and 54 nonsyndromic genes was the most significantly associated and should be given high priority in the future screening of ASD patients. Pathogenic and likely pathogenic variants were detected in 9.5% of cases. Variants in SHANK3 and SHANK2 were the most frequent, especially in females, and occurred in 1.2% of cases. Duplications of 15q11–13 were detected in 0.8% of cases. Variants in CNTNAP2 and MEF2C were correlated with epilepsy/tics in cases. Our findings reveal the diagnostic potential of ASD genetic panel testing and new insights regarding the variant spectrum. Genotype–phenotype correlations may facilitate the diagnosis and management of ASD.     

Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: Genome‐wide association study of both common and rare variants

Attention‐deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case–control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM‐IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome‐wide association analyses were performed using PLINK. SNP‐heritability and SNP‐genetic correlations with ADHD in Caucasians were estimated with genome‐wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein–Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome‐wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP‐heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP‐genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology. © 2013 Wiley Periodicals, Inc.     

Common Variants in KCNQ1 Confer Increased Risk of Type 2 Diabetes and Contribute to the Diabetic Epidemic in East Asians: A Replication and Meta‐Analysis

We aimed to evaluate the effect of four common variants (rs2237892, rs2283228, rs2237895, and rs2237897) in KCNQ1 on susceptibility of type 2 diabetes (T2D) by performing a case‐control study as well as a comprehensive meta‐analysis. We genotyped these four variants in two sets of Chinese Han population, comprising a total of 2533 type 2 diabetic patients and 2643 nondiabetic controls. We also performed a meta‐analysis of our results with published studies in East Asians, meanwhile assessing the population attributable risk (PAR) of these variants. By combining our case‐control sets, a total of 45,204 T2D cases and 42,832 controls were included in the meta‐analyses. The per‐allele ORs ranged from 1.24 to 1.33, and the PARs ranged from 15.8% to 31.8%, with SNP rs2237892 being the most widely studied (16 articles containing a total of 38,338 cases and 35,907 controls), showing strongest association (per‐allele OR: 1.33, 95% CI: 1.28–1.39) and indicating the highest PAR (31.8%). This study confirmed the strong association between common variants in KCNQ1 and risk of T2D. Variants in KCNQ1 were among the leading genetic factors contributing to the overall burden of T2D in East Asians.     

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European‐ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12–30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty‐two disease‐associated SNPs from the PGC‐BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10^?5, AUC = 0.60). In families with a high‐polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at‐risk youth, regardless of affected status, compared to unrelated controls (GEE‐χ² = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease‐associated variants than unrelated controls and first‐degree relatives, and illustrate the potential utility of PRS assessment in a family context. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

     

Association of copy number variation across the genome with neuropsychiatric traits in the general population

Copy number variants (CNVs) are associated with psychiatric conditions in clinical populations. The relationship between rare CNV burden and neuropsychiatric traits in young, general populations is underexplored. A total of 6,807 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied. CNVs were inferred from single nucleotide polymorphism‐array data using PennCNV. After excluding children with known candidate CNVs for schizophrenia (SCZ), rare (<1%) CNV burden (total number of genes affected by CNVs, total length of CNVs, and largest CNV carried) was analyzed in relation to: psychotic experiences (PEs) and anxiety/depression in adolescence; autism spectrum disorder (ASD) and attention‐deficit hyperactivity disorder (ADHD), ASD and ADHD traits, and cognitive measures during childhood. Outcomes were also assessed in relation to known SCZ CNVs. The number of genes affected by rare CNVs was associated with a continuous measure of ASD: the standardized mean difference [SMD] per gene affected was increased by 0.018 [95%CI 0.011,0.025], p = 3e‐07 for duplications and by 0.021 [95%CI 0.010, 0.032], p = 1e‐04 for deletions. In line with our published results on educational attainment in ALSPAC, intelligence quotient (IQ) was associated with CNV burden: the SMD per gene affected was −0.017 [95%CI −0.025, −0.008] p = 1e‐04 for duplications and −0.023 [95%CI −0.037, −0.009], p = .002 for deletions. Associations were also observed for measures of coherence, attention, memory, and social cognition. SCZ‐associated deletions were associated with IQ (SMD: −0.617 [95%CI −0.936, −0.298], p = 2e‐04), but not with PEs or other traits. We found that rare CNV burden and known SCZ candidate CNVs are associated with neuropsychiatric phenotypes in a nonclinically ascertained sample of young people.     

Genetic Variations in Bilirubin Metabolism Genes and Their Association with Unconjugated Hyperbilirubinemia in Adults

Objective : The present study was undertaken to investigate the genotype and allele frequencies of the variants in the four bilirubin metabolism genes (UGT1A1, OATP2, HMOX1, and BLVRA) and their association with hyperbilirubinemia. Material and Methods : Genotyping of 17 genetic variants was performed in 115 adults with hyperbilirubinemia and 150 controls by PCR‐RFLP, GeneScan analysis, and direct DNA sequencing. Results : Genetic polymorphisms of the UGT1A1 promoter, specifically the T‐3279G phenobarbital‐responsive enhancer module and (TA)7 dinucleotide repeat, as well as the intron and coding region variants of the OATP2, HMOX1, and BLVRA genes, were significantly higher among the cases than the controls. Further, nearly 82% of the cases showed the presence of significantly four or more variants as compared to 37% of the controls (P < 0.0001) and the mean total serum bilirubin levels also increased according to the number of variants co‐expressed. Conclusions : This study demonstrates that polymorphisms in the bilirubin metabolism genes had a significant effect on bilirubin levels and could be genetic risk factors for hyperbilirubinemia.     

SCN8A heterozygous variants are associated with anoxic‐epileptic seizures

Anoxic‐epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath‐holding spells triggered by pain or exercise leading to tonic–clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants.     

The relationship between schizophrenia and rheumatoid arthritis revisited: Genetic and epidemiological analyses

Epidemiological studies are inconsistent on the relationship between schizophrenia (SCZ) and rheumatoid arthritis (RA). Several studies have shown that SCZ has a protective effect on RA, with RA occurring less frequently in SCZ cases than would be expected by chance, whilst other studies have failed to replicate this. We sought to test the hypothesis that this effect is due to a protective effect of SCZ risk alleles on RA onset. We first reviewed the literature on the comorbidity of RA and SCZ and performed a meta‐analysis. We then used polygenic risk scoring in an RA case control study in order to investigate the contribution of SCZ risk alleles to RA risk. Meta‐analysis across studies over the past half‐century showed that prevalence of RA in SCZ cases was significantly reduced (OR = 0.48, 95% CI: 0.34–0.67, p < 0.0001). The relationship between SCZ genetic risk and RA status was weak. Polygenic risk of SCZ explained a small (0.1%) and non‐significant (p = 0.085) proportion of variance in RA case control status. This relationship was nominally positive, with RA cases carrying more SCZ risk alleles than controls. The current findings do not support the assertion that the relationship between RA and SCZ is explained by genetic factors, which appear to have little or no effect. The protective effect of SCZ on RA may be due to environmental factors, such as an anti‐inflammatory effect of anti‐psychotic medication or merely due to confounding limitations in study designs. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.     

EYS mutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa

Mutations in Eyes shut homolog (EYS) are one of the most common causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive blinding disorder. The exact function of the EYS protein and the pathogenic mechanisms underlying EYS‐associated RP are still poorly understood, which hampers the interpretation of the causality of many EYS variants discovered to date. We collected all reported EYS variants present in 377 arRP index cases published before June 2017, and uploaded them in the Leiden Open Variation Database ( www.LOVD.nl/EYS ). We also describe 36 additional index cases, carrying 26 novel variants. Of the 297 unique EYS variants identified, almost half (n = 130) are predicted to result in premature truncation of the EYS protein. Classification of all variants using the American College of Medical Genetics and Genomics guidelines revealed that the predicted pathogenicity of these variants cover the complete spectrum ranging from likely benign to pathogenic, although especially missense variants largely fall in the category of uncertain significance. Besides the identification of likely benign alleles previously reported as being probably pathogenic, our comprehensive analysis underscores the need of functional assays to assess the causality of EYS variants, in order to improve molecular diagnostics and counseling of patients with EYS‐associated RP.     

Screening of human LPHN3 for variants with a potential impact on ADHD susceptibility

Attention deficit hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood, and often has effects detectable into adulthood. Advances in genetic linkage and association analysis have begun to elucidate some of the genetic factors underlying this complex disorder. Recently, we identified LPHN3, a novel ADHD susceptibility gene harbored in 4q, and showed that a LPHN3 common haplotype confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Here we present the mutational analysis of the entire coding region of LPHN3 in a cohort of 139 ADHD subjects and 52 controls from across the USA. We identified 21 variants, of which 14 have been reported and 7 are novel. These include 5 missense, 8 synonymous, and 8 intronic changes. Interestingly, neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations, suggesting that non‐coding variations determining the quantity and/or quality of LPHN3 isoforms are the likely contributors to this common behavioral disorder. © 2010 Wiley‐Liss, Inc.     

Evaluation of the relationships of the WBP1L gene with schizophrenia and the general psychopathology scale based on a case–control study

WBP1L is a target of microRNA 137 (miR‐137) and has been considered a candidate gene for schizophrenia (SCZ). To investigate the relationships between WBP1L and SCZ and its related symptom scales, a total of 5,993 Chinese Han subjects, including 2,128 SCZ patients and 3,865 controls, were enrolled. In addition, an independent sample set for replication study including 1,052 SCZ patients and 2,124 controls were also recruited. Thirty‐two tag single nucleotide polymorphisms (SNPs) located within gene region of WBP1L were selected for genotyping and analyzing. The expression quantitative trait loci (eQTL) effects for the targeted SNPs were investigated with gene expression data from multiple human tissues. Rs4147157 (OR = 0.84, p = 1.51 × 10^?5) and rs284854 (OR = 1.14, p = 7.00 × 10^?4) were significantly associated with SCZ disease status and these association signals were replicated in our replication sample. A significant association was identified between rs4147157 and the general (β = ?.66, p = .001) and total (β = ?.8, p = .0042) scores of positive and negative syndrome scale scores in SCZ patients. Both SNPs were significant eQTL for genes around WBP1L in human brain tissues including ARL3 and AS3MT. To conclude, SNPs rs4147157 and rs284854 were associated with SCZ in the Chinese Han population. Additionally, rs4147157 was significantly associated with specific symptom features of SCZ.     

Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.