Pak C Sham

The University of Hong Kong, Hong Kong, Hong Kong

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Publications (622)3162.15 Total impact

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    ABSTRACT: Testis specific protein, Y-encoded-like 2 (TSPYL2) regulates the expression of genes encoding glutamate receptors. Glutamate pathology is implicated in neurodevelopmental conditions such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and schizophrenia. In line with this, a microduplication incorporating the TSPYL2 locus has been reported in people with ADHD. However, the role of Tspyl2 remains unclear. Therefore here we used a Tspyl2 loss-of-function mouse model to directly examine how this gene impacts upon behavior and brain anatomy. We hypothesized that Tspyl2 knockout (KO) would precipitate a phenotype relevant to neurodevelopmental conditions. In line with this prediction, we found that Tspyl2 KO mice were marginally more active, had significantly impaired prepulse inhibition, and were significantly more ‘sensitive’ to the dopamine agonist amphetamine. In addition, the lateral ventricles were significantly smaller in KO mice. These findings suggest that disrupting Tspyl2 gene expression leads to behavioral and brain morphological alterations that mirror a number of neurodevelopmental psychiatric traits.
    No preview · Article · Jan 2016 · Behavior Genetics
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    ABSTRACT: Schizophrenia is a heritable, heterogeneous common psychiatric disorder. In this study, we evaluated the hypothesis that de novo variants (DNVs) contribute to the pathogenesis of schizophrenia. We performed exome sequencing in Chinese patients (N = 45) with schizophrenia and their unaffected parents (N = 90). Forty genes were found to contain DNVs. These genes had enriched transcriptional co-expression profile in prenatal frontal cortex (Bonferroni corrected p < 9.1 × 10(-3)), and in prenatal temporal and parietal regions (Bonferroni corrected p < 0.03). Also, four prenatal anatomical subregions (VCF, MFC, OFC and ITC) have shown significant enrichment of connectedness in co-expression networks. Moreover, four genes (LRP1, MACF1, DICER1 and ABCA2) harboring the damaging de novo mutations are strongly prioritized as susceptibility genes by multiple evidences. Our findings in Chinese schizophrenic patients indicate the pathogenic role of DNVs, supporting the hypothesis that schizophrenia is a neurodevelopmental disease.
    Full-text · Article · Jan 2016 · Scientific Reports
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    ABSTRACT: A polygenic score is commonly derived using genome-wide genotype data to summarize the genetic contribution to a particular disease at the individual level. Usually it is constructed as a linear combination of SNP genotype weighted by the SNP-wise regression coefficient of the SNP to the phenotype using SNPs with p values smaller than a particular threshold. Commonly a range of thresholds are used which can pose problems with multiple comparisons as well as over-fitting. Here, an alternative weighting scheme is proposed, making use of the local true discovery rate, estimated from summary statistics. Two methods of estimation are proposed-maximum likelihood and kernel density estimation. Simulation studies using real and artificial data suggest this new weighting scheme is highly comparable with standard polygenic scores using the best possible p value threshold in prediction, even though this threshold is not normally known in practice.
    No preview · Article · Jan 2016 · Behavior Genetics
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    Full-text · Dataset · Jan 2016
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    ABSTRACT: The genetic and environmental contributions to the variation and longitudinal stability in childhood aggressive behavior were assessed in two large twin cohorts, the Netherlands Twin Register (NTR), and the Twins Early Development Study (TEDS; United Kingdom). In NTR, maternal ratings on aggression from the Child Behavior Checklist (CBCL) were available for 10,765 twin pairs at age 7, for 8,557 twin pairs at age 9/10, and for 7,176 twin pairs at age 12. In TEDS, parental ratings of conduct disorder from the Strength and Difficulty Questionnaire (SDQ) were available for 6,897 twin pairs at age 7, for 3,028 twin pairs at age 9 and for 5,716 twin pairs at age 12. In both studies, stability and heritability of aggressive behavioral problems was high. Heritability was on average somewhat, but significantly, lower in TEDS (around 60%) than in NTR (between 50% and 80%) and sex differences were slightly larger in the NTR sample. In both studies, the influence of shared environment was similar: in boys shared environment explained around 20% of the variation in aggression across all ages while in girls its influence was absent around age 7 and only came into play at later ages. Longitudinal genetic correlations were the main reason for stability of aggressive behavior. Individual differences in CBCL-Aggressive Behavior and SDQ-Conduct disorder throughout childhood are driven by a comparable but significantly different genetic architecture.
    No preview · Article · Jan 2016 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    ABSTRACT: Oxytocin has been suggested as a promising new treatment for neurodevelopmental disorders. However, important gaps remain in our understanding of its mode of action, in particular, to what extent oxytocin modulates social and non-social behaviours and whether its effects are generalizable across both sexes. Here we investigated the effects of a range of oxytocin doses on social and non-social behaviours in C57BL/6N mice of both sexes. As the striatum modulates social and non-social behaviours, and is implicated in neurodevelopmental disorders, we also conducted a pilot exploration of changes in striatal protein expression elicited by oxytocin. Oxytocin increased prepulse inhibition of startle but attenuated the recognition memory in male C57BL/6N mice. It increased social interaction time and suppressed the amphetamine locomotor response in both sexes. The striatum proteome following oxytocin exposure could be clearly discriminated from saline controls. With the caveat that these results are preliminary, oxytocin appeared to alter individual protein expression in directions similar to conventional anti-psychotics. The proteins affected by oxytocin could be broadly categorized as those that modulate glutamatergic, GABAergic or dopaminergic signalling and those that mediate cytoskeleton dynamics. Our results here encourage further research into the clinical application of this peptide hormone, which may potentially extend treatment options across a spectrum of neurodevelopmental conditions.
    Full-text · Article · Dec 2015 · PLoS ONE
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    ABSTRACT: Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10-7), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci - PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser - also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.
    Full-text · Article · Dec 2015 · Nature Communications
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    Full-text · Article · Dec 2015
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    ABSTRACT: Genome-wide association studies (GWASs), now as a routine approach to study single-nucleotide polymorphism (SNP)-trait association, have uncovered over ten thousand significant trait/disease associated SNPs (TASs). Here, we updated GWASdb (GWASdb v2, http://jjwanglab.org/gwasdb) which provides comprehensive data curation and knowledge integration for GWAS TASs. These updates include: (i) Up to August 2015, we collected 2479 unique publications from PubMed and other resources; (ii) We further curated moderate SNP-trait associations (P-value < 1.0×10-3) from each original publication, and generated a total of 252 530 unique TASs in all GWASdb v2 collected studies; (iii) We manually mapped 1610 GWAS traits to 501 Human Phenotype Ontology (HPO) terms, 435 Disease Ontology (DO) terms and 228 Disease Ontology Lite (DOLite) terms. For each ontology term, we also predicted the putative causal genes; (iv) We curated the detailed sub-populations and related sample size for each study; (v) Importantly, we performed extensive function annotation for each TAS by incorporating gene-based information, ENCODE ChIP-seq assays, eQTL, population haplotype, functional prediction across multiple biological domains, evolutionary signals and disease-related annotation; (vi) Additionally, we compiled a SNP-drug response association dataset for 650 pharmacogenetic studies involving 257 drugs in this update; (vii) Last, we improved the user interface of website.
    Full-text · Article · Nov 2015 · Nucleic Acids Research
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    Jia-En Deng · Pak C Sham · Miao-Xin Li
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    ABSTRACT: The reference single nucleotide polymorphism (rs) ID in dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) is a key resource identifier, which is widely used in human genetics and genomics studies. However, its application is often complicated by the varied IDs of different versions. Here, we developed a user-friendly tool, SNPTracker, for comprehensively tracking and unifying the rs IDs and genomic coordinates of massive sequence variants at a time. It worked perfectly, and had much higher accuracy and capacity than two alternative utilities in our proof-of-principle examples. SNPTracker will greatly facilitate genetic data exchange and integration in the postgenome-wide association study era.
    Preview · Article · Nov 2015 · G3-Genes Genomes Genetics
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    ABSTRACT: Objective: Multiple etiological and prognostic factors have been implied in schizophrenia and its outcome. Advanced paternal age has been reported as a risk factor in schizophrenia. Whether this may affect schizophrenia outcome was not previously studied. We hypothesized that advanced paternal age may have a negative effect on the outcome of relapse in schizophrenia. Method: We interviewed 191 patients with first-episode schizophrenia and their relatives for parental ages, sociodemographic factors at birth, birth rank, family history of psychotic disorders, and obstetric complications. The outcome measure was the presence of relapse at the end of the first year of treatment. Results: In the 1-year follow-up period, 42 (22%) patients experienced 1 or more relapses. The mean paternal age was 34.62 years (SD 7.69). Patients who relapsed had significantly higher paternal age, poorer medication adherence, were female, and were hospitalized at onset, compared with patients who did not relapse. A multivariate regression analysis showed that advanced paternal age (OR 1.05, 95% CI 1.01 to 1.10), medication nonadherence (OR 2.37, 95% CI 1.12 to 4.99), and female sex (OR 2.44, 95% CI 1.14 to 5.24) independently contributed to a higher risk of relapse. Analysis between different paternal age groups found a significantly higher relapse rate with paternal age over 40. Conclusions: Advanced paternal age is found to be modestly but significantly related to more relapses, and such an effect is the strongest at a cut-off of paternal age of 40 years or older. The effect is less likely to be mediated through less effective parental supervision or nonadherence to medication. Other possible biological mechanisms need further explorations.
    No preview · Article · Oct 2015 · Canadian journal of psychiatry. Revue canadienne de psychiatrie
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    Q Li · Y O Leung · I Zhou · L C Ho · W Kong · P Basil · R Wei · S Lam · X Zhang · A C K Law · S E Chua · P C Sham · E X Wu · G M McAlonan
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    ABSTRACT: Prenatal exposure to maternal immune activation (MIA) increases the risk of schizophrenia and autism in the offspring. The MIA rodent model provides a valuable tool to directly test the postnatal consequences of exposure to an early inflammatory insult; and examine novel preventative strategies. Here we tested the hypotheses that behavioural differences in the MIA mouse model are accompanied by in vivo and ex vivo alterations in brain biochemistry; and that these can be prevented by a post-weaning diet enriched with n-3 polyunsaturated fatty acid (PUFA). The viral analogue PolyI:C (POL) or saline (SAL) was administered to pregnant mice on gestation day 9. Half the resulting male offspring (POL=21; SAL=17) were weaned onto a conventional lab diet (n-6 PUFA); half were weaned onto n-3 PUFA-enriched diet. In vivo magnetic resonance spectroscopy measures were acquired prior to behavioural tests; glutamic acid decarboxylase 67 (GAD67) and tyrosine hydroxylase protein levels were measured ex vivo. The main findings were: (i) Adult MIA-exposed mice fed a standard diet had greater N-acetylaspartate/creatine (Cr) and lower myo-inositol/Cr levels in the cingulate cortex in vivo. (ii) The extent of these metabolite differences was correlated with impairment in prepulse inhibition. (iii) MIA-exposed mice on the control diet also had higher levels of anxiety and altered levels of GAD67 ex vivo. (iv) An n-3 PUFA diet prevented all the in vivo and ex vivo effects of MIA observed. Thus, n-3 PUFA dietary enrichment from early life may offer a relatively safe and non-toxic approach to limit the otherwise persistent behavioural and biochemical consequences of prenatal exposure to inflammation. This result may have translational importance.
    Full-text · Article · Sep 2015 · Translational Psychiatry
  • Johnny Sh Kwan · Miao-Xin Li · Jia-En Deng · Pak C Sham
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    ABSTRACT: Imputing individual-level genotypes (or genotype imputation) is now a standard procedure in genome-wide association studies (GWAS) to examine disease associations at untyped common genetic variants. Meta-analysis of publicly available GWAS summary statistics can allow more disease-associated loci to be discovered, but these data are usually provided for various variant sets. Thus imputing these summary statistics of different variant sets into a common reference panel for meta-analyses is impossible using traditional genotype imputation methods. Here we develop a Fast and Accurate P-value Imputation (FAPI) method that utilizes summary statistics of common variants only. Its computational cost is linear with the number of untyped variants and has similar accuracy compared with IMPUTE2 with prephasing, one of the leading methods in genotype imputation. In addition, based on the FAPI idea, we develop a metric to detect abnormal association at a variant and showed that it had a significantly greater power compared with LD-PAC, a method that quantifies the evidence of spurious associations based on likelihood ratio. Our method is implemented in a user-friendly software tool, which is available at http://statgenpro.psychiatry.hku.hk/fapi.European Journal of Human Genetics advance online publication, 26 August 2015; doi:10.1038/ejhg.2015.190.
    No preview · Article · Aug 2015 · European journal of human genetics: EJHG
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    ABSTRACT: Previous genome-wide association studies (GWAS), which were mainly based on single variant analysis, have identified many susceptibility loci for systemic lupus erythematosus (SLE). However, the genetic architecture of this complex disease is far from understood. A gene-based analysis may help identify novel loci by considering global evidence of association from a gene or a genomic region rather than focusing on evidence from individual variants. Based on meta-analysis results of two SLE GWASs, we performed gene- and region-based analysis followed by replication with a total of 4,626 cases and 7,466 controls of Asian ancestry. Allelic differential expression was measured by pyrosequencing. Over half of the reported SLE susceptibility loci showed evidence of independent effects, which is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel susceptibility gene for SLE with several SNPs contributing independently to disease association. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in PBMCs of heterozygous healthy controls. Several other associated SNPs may also regulate ANXA6 expression based on data from public databases. Higher expression of ANXA6 in SLE cases was also reported previously. Our study demonstrated the merit of gene-based analysis in identifying novel susceptibility loci, especially those with independent effects, and also demonstrated a widespread presence of independent contributors in susceptibility genes for SLE. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
    No preview · Article · Jul 2015 · Arthritis and Rheumatology
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    ABSTRACT: Diffuse oesophageal leiomyomatosis (DOL) is a rare disorder characterized by tumorous overgrowth of the muscular wall of the oesophagus. DOL is present in 5 % of Alport syndrome (AS) patients. AS is a rare hereditary disease that involves varying degrees of hearing impairment, ocular changes and progressive glomerulonephritis leading to renal failure. In DOL-AS patients, the genetic defect consists of a deletion involving the COL4A5 and COL4A6 genes on the X chromosome. We report a two-generation family (4 individuals; parents and two children, one male and one female) with two members (mother and son) affected with oesophageal leiomyomatosis. Signs of potential renal failure, which characterizes AS, were only apparent in the index patient (son) 2 years and three months after the initial diagnosis of DOL. Blood DNA from the four family members were submitted to exome sequencing and array genotyping to perform a genome wide screening for disease causal single nucleotide (SN) and copy number (CN) variations. Analyses revealed a new 40kb deletion encompassing from intron 2 of COL4A5 to intron 1 of COL4A6 at Xq22.3. The breakpoints were also identified. Possible confounding pathogenic exonic variants in genes known to be involved in other extracellular matrices disorders were also shared by the two affected individuals. Meticulous analysis of the maternal DNA revealed a case of gonosomal mosaicism. This is the first report of gonadosomal mosaicism associated to DOL-AS.
    Full-text · Article · Jul 2015 · BMC Medical Genetics

  • No preview · Conference Paper · Jul 2015
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    ABSTRACT: Over a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions. To answer this question, we investigated how well the current archive of genetic evidence predicts drug mechanisms. We found that, among well-studied indications, the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas. We estimate that selecting genetically supported targets could double the success rate in clinical development. Therefore, using the growing wealth of human genetic data to select the best targets and indications should have a measurable impact on the successful development of
    Full-text · Article · Jun 2015 · Nature Genetics
  • Jiang Li · Pak Chung Sham · Youqiang Song · Miaoxin Li
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    ABSTRACT: Set-based association tests, combining a set of single-nucleotide polymorphisms into a unified test, have become important approaches to identify weak-effect or low-frequency risk loci of complex diseases. However, there is no comprehensive and user-friendly tool to estimate power of set-based tests for study design. We developed a simulation tool to estimate statistical power of multiple representative set-based tests (SPS). SPS has a graphic interface to facilitate parameter settings and result visualization. Advanced functions include loading real genotypes to define genetic architecture, set-based meta-analysis for risk loci with or without heterogeneity, and parallel simulations. In proof-of-principle examples, SPS took no more than 3 sec on average to estimate the power in a conventional setting. The SPS has been integrated into a user-friendly software tool (KGG) as an independent functional module and it is freely available at http://statgenpro.psychiatry.hku.hk/limx/kgg/. © 2015 WILEY PERIODICALS, INC.
    No preview · Article · May 2015 · Genetic Epidemiology
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    ABSTRACT: Recent founder mutations may play important roles in complex diseases and Mendelian disorders. Detecting shared haplotypes that are identical by descent (IBD) could facilitate discovery of these mutations. Several programs address this, but are usually limited to detecting pair-wise shared haplotypes and not providing a comparison of cases and controls. We present a novel algorithm and software package, HaploShare, which detects extended haplotypes that are shared by multiple individuals, and allows comparisons between cases and controls. Testing on simulated and real cases demonstrated significant improvements in detection power and reduction of false positive rate by HaploShare relative to other programs. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0662-9) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2015 · Genome biology

  • No preview · Article · May 2015 · Maturitas

Publication Stats

40k Citations
3,162.15 Total Impact Points

Institutions

  • 2004-2016
    • The University of Hong Kong
      • • Department of Psychiatry
      • • Centre for Genomic Sciences
      • • Department of Medicine
      Hong Kong, Hong Kong
  • 2009-2015
    • Lands Department of The Government of the Hong Kong Special Administrative Region
      Hong Kong, Hong Kong
  • 2004-2014
    • Queen Mary Hospital
      Hong Kong, Hong Kong
  • 2011
    • The Hong Kong Polytechnic University
      • Department of Health Technology and Informatics
      Hong Kong, Hong Kong
  • 2010
    • ICL
      Londinium, England, United Kingdom
  • 1992-2008
    • King's College London
      • • MRC Social, Genetic and Developmental Psychiatry Centre
      • • Department of Psychological Medicine
      • • Institute of Psychiatry
      Londinium, England, United Kingdom
  • 2006
    • Toronto Western Hospital
      Toronto, Ontario, Canada
    • University of Oulu
      • Department of Medical Biochemistry and Molecular Biology
      Uleoborg, Northern Ostrobothnia, Finland
    • National University of Ireland, Galway
      • Department of Psychiatry
      Gaillimh, Connaught, Ireland
  • 2003-2006
    • University of Cambridge
      • Department of Psychiatry
      Cambridge, England, United Kingdom
    • Chang Gung Memorial Hospital
      • Department of Psychiatry
      T’ai-pei, Taipei, Taiwan
    • University College London
      • Department of Epidemiology and Public Health
      London, ENG, United Kingdom
  • 1999-2006
    • University of London
      Londinium, England, United Kingdom
    • Sapienza University of Rome
      Roma, Latium, Italy
    • University of Missouri
      Columbia, Missouri, United States
  • 1998-2006
    • London Research Institute
      Londinium, England, United Kingdom
  • 2005
    • Shanghai Jiao Tong University
      • Bio-X Institute
      Shanghai, Shanghai Shi, China
    • Queen Mary, University of London
      • Centre for Psychiatry
      Londinium, England, United Kingdom
  • 1996-2005
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
    • Clinique médicale et pédagogique Dupré
      Île-de-France, France
  • 1998-2004
    • The Kings College
      Колумбия, Tennessee, United States
  • 1997-2003
    • Maastricht University
      • Department of Epidemiology
      Maastricht, Provincie Limburg, Netherlands
    • Teikyo University
      Edo, Tōkyō, Japan
  • 2002
    • University of South Wales
      Понтиприте, Wales, United Kingdom
  • 2000-2002
    • Instituto Nacional de Psiquiatría
      Ciudad de México, Mexico City, Mexico
    • Sichuan University
      Hua-yang, Sichuan, China
  • 2001
    • University of Colorado at Boulder
      Boulder, Colorado, United States
    • UK Energy Research Centre
      Londinium, England, United Kingdom
  • 1995-1999
    • New South Wales Institute of Psychiatry
      Sydney, New South Wales, Australia
    • University of Essex
      Colchester, England, United Kingdom
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
    • St. James's Hospital
      Dublin, Leinster, Ireland
  • 1993-1995
    • Virginia Commonwealth University
      • Department of Psychiatry
      Ричмонд, Virginia, United States
  • 1991
    • University of Nottingham
      • Division of Psychiatry and Applied Psychology
      Nottigham, England, United Kingdom