Pak Sham

The University of Hong Kong, Hong Kong, Hong Kong

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Publications (278)1470.98 Total impact

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    ABSTRACT: In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions.Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.152.
    Molecular Psychiatry 12/2014; · 15.15 Impact Factor
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    ABSTRACT: There is an urgent need for the identification of Alzheimer's disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10-0.48, P=4.19E-04; ChE 34:0, OR=0.152, 95% CI=0.05-0.37, P=2.90E-04; ChE 34:6, OR=0.126, 95% CI=0.03-0.35, P=5.40E-04; ChE 32:4, OR=0.056, 95% CI=0.01-0.24, P=6.56E-04 and ChE 33:6, OR=0.205, 95% CI=0.06-0.50, P=2.21E-03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.
    Translational Psychiatry. 10/2014;
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    ABSTRACT: Objective: Chronic periodontitis is the most prevalent form of periodontitis, which has been suggested to have a genetic predisposition. However, genetic risk factors associated with chronic periodontitis have not been addressed in Chinese. As such, this study investigated the genetic polymorphisms which may be associated with chronic periodontitis using a genome wide association study (GWAS) approach in Southern Chinese subjects. Method: The subjects were recruited from the Hong Kong Disc Degeneration Cohort, a population-based study of Southern Chinese consisting of 3,500 volunteer subjects in which whole-genome DNA samples were genotyped by Illuminar SNP arrays in a large subset of subjects. In this pilot study, dental examinations were performed and periodontal conditions were assessed in 363 subjects (226 females, 137 males; age range: 40-72 years of age) out of this cohort based on the CDC/AAP periodontitis classification and mean probing attachment level (MPAL) parameters. Statistical analysis addressed the association between chronic periodontitis classifications and single nucleotide polymorphisms (SNPs). Result: Following quality control, 778,667 SNPs have been selected for GWAS analysis. Adjusting for age and gender, SNPs in 5 genes were associated with CDC/AAP periodontal status and MPAL (p =1.12×10-5~ 9.69×10-5). Conclusion: This is the first GWAS study on chronic periodontitis in a Southern Chinese population. This pilot study noted 5 genes that may be associated with this condition. Although our findings are preliminary, they substantiate the need to further pursue larger scale studies with greater sample size to assess the genetics of chronic periodontitis and further validate the preliminary findings. Identifying genetic risk factors of chronic periodontitis will further elaborate on understanding the biological implications of the disease with hopes to lead to preventative, diagnostic and prognostic platforms.
    2014 IADR/PER Congress; 09/2014
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    ABSTRACT: Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.
    PLoS Medicine 09/2014; 11(9):e1001713. · 15.25 Impact Factor
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    ABSTRACT: Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.
    Neurobiology of Aging 07/2014; · 4.85 Impact Factor
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    ABSTRACT: Background/Aims: The Remission in Schizophrenia Working Group has defined remission as 'a low-mild symptom intensity level, maintained for a minimum of 6 months, where such symptoms do not affect an individual's behaviour' [Andreasen et al.: Am J Psychiatry 2005;162:441-449]. Since brain morphology relates to symptomatology, treatment and illness progression, MRI may assist in predicting remission. Methods: Thirty-nine patients newly diagnosed with DSM-IV schizophrenia underwent MRI brain scan prior to antipsychotic exposure. The Global Assessment of Functioning (GAF) score was entered into a voxel-based analysis to evaluate its relationship with cerebral grey matter volume from the baseline MRI. We entered age, total intracranial volume and intake GAF score as co-variates. Males and females were analysed separately because gender is a potent determinant of outcome. Results: Males had lower GAF scores than females, both at intake and at 1 year. Males comprised only 40% (12 out of 39) of the early remission group. For females only, early remission was strongly and positively correlated with bilateral lentiform and striatal volumes. For males, there was no such relationship. Conclusion: Larger striato-thalamic volume correlated with early remission in females only. These baseline MRI findings were unlikely to be confounded by antipsychotic treatment and chronicity. These brain morphological markers show gender dimorphism and may assist in the prediction of early remission in newly diagnosed schizophrenia. © 2014 S. Karger AG, Basel.
    Neuropsychobiology 06/2014; 69(4):243-248. · 2.30 Impact Factor
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    ABSTRACT: Background: Human epidemiological studies have linked labor and delivery complications leading to hypoxia/ischemia at birth with increased risk of neurodevelopmental disorders such as schizophrenia and autism. This can be modeled experimentally by exposing rat pups to 15 min of intrauterine anoxia during Caesarean section birth causing behavioral anomalies relevant to neurodevelopmental disorders such as autism. This model also affords us the opportunity to directly examine brain cellular mechanisms modified by this perinatal assault. Objectives: To carry out a direct experimental test of the impact of perinatal asphyxia on protein expression in the postnatal prefrontal cortex. Methods: We used two dimensional differential in-gel electrophoresis and mass spectrometry, with targeted western blot analyses for confirmation, to quantify the proteomic profile of the prefrontal cortex - a region strongly implicated in autism - in 6 (adolescent) and 12 (adult) week old rats previously exposed to perinatal asphyxia. Control groups included pups delivered by C-section without anoxia and pups delivered vaginally. Group differences in global protein expression were examined using a partial least squares discriminative analysis ( SIMCA 9.0 software, Umetrics, Sweden; PLS-DA) and the expression differences of individual proteins examined using Analysis of Variance run on Progenesis software (initial screen across all groups, significance threshold set at p <0.1; post-hoc analysis of group contrasts, significance threshold set at p <0.05). Finally western blot was used to confirm gel-differences in selected proteins. Results: Multivariate analyses of protein spots present in at least 75% of 60 images indicated a clear separation on the basis of protein expression between 6 and 12 week old animals and between the 3 experimental groups. Proteomic profiling revealed a significant up-regulation of mitochondrial enzymes such as isocitrate dehydrogenase, cytosolic malate dehydrogenase, and NADH dehydrogenase and significant down-regulation of signaling proteins such as 14-3-3 and structural proteins such as neurofilament light polypeptide (NEFL) in the perinatally asphyxiated group. Western blot confirmed the expression of isocitrate dehydrogenase was significantly up-regulated whereas, 14-3-3 zeta and NEFL were significantly down-regulated, in the asphyxia group across all age groups (p<0.05). Conclusions: The differences elicited by perinatal asphyxia are consistent with emerging evidence for mitochondrial dysregulation in neurodevelopmental disorders, and may in time contribute novel biomarkers and fresh targets for prevention or treatment.
    2014 International Meeting for Autism Research; 05/2014
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.
    Journal of Medical Genetics 04/2014; · 5.64 Impact Factor
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    ABSTRACT: Alterations in gray matter (GM) are commonly observed in schizophrenia. Accumulating studies suggest that the brain changes associated with schizophrenia are distributed rather than focal, involving interconnected networks of areas as opposed to single regions. In the current study we aimed to explore GM volume (GMV) changes in a relatively large sample of treatment-naive first-episode schizophrenia (FES) patients using optimized voxel-based morphometry (VBM) and covariation analysis. High-resolution T1-weighted images were obtained using 3.0-T magnetic resonance imaging (MRI) from 86 first-episode drug-naive patients with schizophrenia and 86 age- and gender-matched healthy volunteers. Symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS). GMV was assessed using optimized VBM and in 16 regions of interest (ROIs), selected on the basis of a previous meta-analysis. The relationships between GMVs in the ROIs were examined using an analysis of covariance (ANCOVA). The VBM analysis revealed that first-episode patients showed reduced GMV in the hippocampus bilaterally. The ROI analysis identified reductions in GMV in the left inferior frontal gyrus, bilateral hippocampus and right thalamus. The ANCOVA revealed different patterns of regional GMV correlations in patients and controls, including of inter- and intra-insula, inter-amygdala and insula-postcentral gyrus connections. Schizophrenia involves regional reductions in GMV and changes in GMV covariance in the insula, amygdala and postcentral gyrus. These findings were evident at the onset of the disorder, before treatment, and therefore cannot be attributable to the effects of chronic illness progression or medication.
    Psychological Medicine 01/2014; · 5.43 Impact Factor
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    ABSTRACT: There is mixed evidence concerning cognitive function and heroin dependence. In this study, abstinent heroin-dependent individuals (n = 86) and age- and sex-matched non-drug-using controls (n = 88) were compared on self-report measures of impulsivity and computerized assessments of cognitive function. Abstinent heroin-dependent individuals reported greater motor impulsivity and experience seeking and showed functional weaknesses in cognitive ability, including impulsivity and distractibility (d = 0.28 to 0.49), but not decision making or working memory. Self-reported impulsivity was uncorrelated with cognitive function. These results suggest underlying brain-related factors in heroin dependence and have implications for therapeutic intervention.
    Journal of Clinical and Experimental Neuropsychology 09/2013; · 2.16 Impact Factor
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    ABSTRACT: Heroin abuse and natural aging exert common influences on immunological cell functioning. This observation led to a recent and untested idea that aging may be accelerated in abusers of heroin. We examined this claim by testing whether heroin use is associated with premature aging at both cellular and brain system levels. A group of abstinent heroin users (n=33) and matched healthy controls (n=30) were recruited and measured on various biological indicators of aging. These measures included peripheral blood telomerase activity, which reflects cellular aging, and both structural and functional measures of brain magnetic resonance imaging. We found that heroin users were characterized by significantly low telomerase activity (0.21 vs 1.78; 88% reduction; t(61)=6.96, P<0.001; 95% confidence interval=1.12-2.02), which interacted with heroin use to affect the structural integrity of gray and white matter of the prefrontal cortex (PFC; AlphaSim corrected P<0.05), a key brain region implicated in aging. Using the PFC location identified from the structural analyses as a 'seed' region, it was further revealed that telomerase activity interacted with heroin use to impact age-sensitive brain functional networks (AlphaSim corrected P<0.05), which correlated with behavioral performance on executive functioning, memory and attentional control (Pearson correlation, all P<0.05). To our knowledge, this study is the first to attempt a direct integration of peripheral molecular, brain system and behavioral measures in the context of substance abuse. The present finding that heroin abuse is associated with accelerated aging at both cellular and brain system levels is novel and forms a unique contribution to our knowledge in how the biological processes of drug abusers may be disrupted.
    Translational psychiatry. 05/2013; 3:e260.
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    ABSTRACT: BACKGROUND: It is not clear whether the progressive changes in brain microstructural deficits documented in previous longitudinal magnetic resonance imaging (MRI) studies might be due to the disease process or to other factors such as medication. It is important to explore the longitudinal alterations in white-matter (WM) microstructure in antipsychotic-naive patients with first-episode schizophrenia during the very early phase of treatment when relatively 'free' from chronicity. Method Thirty-five patients with first-episode schizophrenia and 22 healthy volunteers were recruited. High-resolution diffusion tensor imaging (DTI) was obtained from participants at baseline and after 6 weeks of treatment. A 'difference map' for each individual was calculated from the 6-week follow-up fractional anisotropy (FA) of DTI minus the baseline FA. Differences in Positive and Negative Syndrome Scale (PANSS) scores and Global Assessment of Functioning (GAF) scores between baseline and 6 weeks were also evaluated and expressed as a 6-week/baseline ratio. RESULTS: Compared to healthy controls, there was a significant decrease in absolute FA of WM around the bilateral anterior cingulate gyrus and the right anterior corona radiata of the frontal lobe in first-episode drug-naive patients with schizophrenia following 6 weeks of treatment. Clinical symptoms improved during this period but the change in FA did not correlate with the changes in clinical symptoms or the dose of antipsychotic medication. CONCLUSIONS: During the early phase of treatment, there is an acute reduction in WM FA that may be due to the effects of antipsychotic medications. However, it is not possible to entirely exclude the effects of underlying progression of illness.
    Psychological Medicine 02/2013; · 5.43 Impact Factor
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    ABSTRACT: Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n=8) or anxiety disorders (n=3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, P(SR) and P(OR), were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant P(SR)P-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.
    European journal of human genetics: EJHG 04/2012; 20(10):1078-84. · 3.56 Impact Factor
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    ABSTRACT: A study was conducted to validate the most significant single nucleotide polymorphism (SNP) from a genome-wide association study of Japanese adolescent idiopathic scoliosis (AIS) patients in an independent southern Chinese population. In total, 300 AIS patients fulfilled the clinical criteria and 788 controls with MRI scans of the spine were included in the replication study. We employed case-control analysis to study the association of SNP rs11190870 near LBX1 (ladybird homeobox 1) with AIS in a southern Chinese population. The results suggest that SNP rs11190870 is significantly associated with AIS (P=9.1 × 10(-10); odds ratio=1.85; 95% confidence interval=1.52-2.25). The results of this study confirm that SNP rs11190870 is associated with AIS.
    Journal of Human Genetics 02/2012; 57(4):244-6. · 2.53 Impact Factor
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    ABSTRACT: Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future. The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis. We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA). Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the -2,327 bp upstream (P = 6.8 × 10(-4)) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA. Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.
    Osteoporosis International 01/2012; 23(7):1877-87. · 4.04 Impact Factor
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.
    Lupus 01/2012; 21(1):75-83. · 2.48 Impact Factor
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    ABSTRACT: FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians. All studies published on the association between FTO-rs9939609 (or proxy [r (2) > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes. The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10(-19)), overweight by 1.13-fold/allele (p = 1.0 × 10(-11)) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10(-8)). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10(-5)). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m(2) per allele (p = 2.8 × 10(-17)), WHR by 0.003/allele (p = 1.2 × 10(-6)), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12-20%) than South Asians (30-33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations. FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
    Diabetologia 11/2011; 55(4):981-95. · 6.88 Impact Factor
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    ABSTRACT: The study of endophenotypes may be a viable strategy to tackle the genetic complexity and phenotypic heterogeneity of psychosis, but this research direction is relatively under-developed in China as compared to Western countries. We have recently initiated one of the first family studies of endophenotypes for psychosis in China. Patients entering an established early psychosis intervention service are recruited into this research project for phenotyping, endophenotyping and genotyping. At the endophenotypic level, four domains (neurological soft signs, neurocognition of prospective memory, social cognition of facial emotion recognition, and affective cognition of anticipatory and consummatory pleasure) are studied in the sample of patients with psychosis and their unaffected siblings. This article illustrates the benefit of a research-oriented clinical programme and its findings based on the data collected as of early 2011. Keywordspsychosis–endophenotypes–neuropsychology–social cognition
    Chinese Science Bulletin 11/2011; 56(32):3394-3397. · 1.37 Impact Factor
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    ABSTRACT: Brain structure appears to alter after antipsychotic administration, but it is unknown whether these alterations are associated with improvement of psychopathology in patients with schizophrenia. In this study, the authors explore this relationship. Altogether, 66 first-episode, drug-naive patients with schizophrenia and 23 well-matched healthy controls underwent brain magnetic resonance imaging scans at baseline. All 23 healthy controls and 42 of the patients were rescanned after 6 weeks follow-up. The patients received regular antipsychotic treatment during the 6-week period and their psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and 6 weeks. The difference in PANSS scores between baseline and 6 weeks was expressed as a ratio of the scores at baseline - 'PANSS reduction ratio'. A modified tensor-based morphometry procedure was applied to analyse longitudinal images. Correlations between regional volume changes, PANSS reduction ratio and antipsychotic drug dosages were explored. Compared with healthy controls, there was a significant increase in grey-matter volume of the right putamen in patients after 6 weeks treatment. This volume change was positively correlated with a positive PANSS reduction score but not related to drug dosages. Putaminal volume increased after 6 weeks antipsychotic treatment in first-episode schizophrenia. The increased volume was closely correlated with improved psychopathology, suggesting the putamen might be a biomarker to predict the treatment response in schizophrenia.
    Psychological Medicine 10/2011; 42(7):1475-83. · 5.43 Impact Factor
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    ABSTRACT: We investigated cerebral structural connectivity and its relationship to symptoms in never-medicated individuals with first-onset schizophrenia using diffusion tensor imaging (DTI). Method: We recruited subjects with first episode DSM-IV schizophrenia who had never been exposed to antipsychotic medication (n=34) and age-matched healthy volunteers (n=32). All subjects received DTI and structural magnetic resonance imaging scans. Patients' symptoms were assessed on the Positive and Negative Syndrome Scale. Voxel-based analysis was performed to investigate brain regions where fractional anisotropy (FA) values significantly correlated with symptom scores. In patients with first-episode schizophrenia, positive symptoms correlated positively with FA scores in white matter associated with the right frontal lobe, left anterior cingulate gyrus, left superior temporal gyrus, right middle temporal gyrus, right middle cingulate gyrus, and left cuneus. Importantly, FA in each of these regions was lower in patients than controls, but patients with more positive symptoms had FA values closer to controls. We found no significant correlations between FA and negative symptoms. The newly-diagnosed, neuroleptic-naive patients had lower FA scores in the brain compared with controls. There was positive correlation between FA scores and positive symptoms scores in frontotemporal tracts, including left fronto-occipital fasciculus and left inferior longitudinal fasciculus. This implies that white matter dysintegrity is already present in the pre-treatment phase and that FA is likely to decrease after clinical treatment or symptom remission.
    Psychological Medicine 08/2011; 41(8):1709-19. · 5.43 Impact Factor

Publication Stats

13k Citations
1,470.98 Total Impact Points


  • 2002–2014
    • The University of Hong Kong
      • • State Key Laboratory of Brain and Cognitive Sciences
      • • Department of Psychiatry
      • • Department of Biochemistry
      Hong Kong, Hong Kong
  • 2008–2011
    • Harvard Medical School
      • Department of Psychiatry
      Boston, MA, United States
  • 2005–2011
    • Sichuan University
      • State Key Laboratory of Biotherapy
      Hua-yang, Sichuan, China
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom
  • 2010
    • Brigham and Women's Hospital
      • Department of Medicine
      Cambridge, MA, United States
  • 1995–2010
    • King's College London
      • • Institute of Psychiatry
      • • Department of Psychological Medicine
      Londinium, England, United Kingdom
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
  • 2005–2009
    • Shanghai Jiao Tong University
      • Bio-X Institute
      Shanghai, Shanghai Shi, China
  • 2007
    • McLean Hospital
      • Psychology Research Laboratory
      Cambridge, Massachusetts, United States
  • 2004–2006
    • Queen Mary Hospital
      Hong Kong, Hong Kong
    • Harvard University
      Cambridge, Massachusetts, United States
    • Trinity College Dublin
      • Department of Genetics
      Dublin, L, Ireland
    • Maastricht University
      • Department of Epidemiology
      Maastricht, Provincie Limburg, Netherlands
  • 2003–2004
    • King College
      Georgia, United States
    • Chang Gung Memorial Hospital
      • Department of Psychiatry
      Taipei, Taipei, Taiwan
  • 2001–2002
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 1992–2001
    • London Research Institute
      Londinium, England, United Kingdom
  • 1995–2000
    • New South Wales Institute of Psychiatry
      Sydney, New South Wales, Australia
  • 1999
    • University of Wales
      Cardiff, Wales, United Kingdom
  • 1996–1998
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
    • Clinique médicale et pédagogique Dupré
      Île-de-France, France
  • 1993–1995
    • Virginia Commonwealth University
      • Department of Psychiatry
      Richmond, VA, United States