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Biomedical subjects

Pak Sham

Publications and source records attributed to Pak Sham.

At least 19 recordsLinked to original sources
PubMed2007

Genetic overlap between bipolar illness and event-related potentials.

BACKGROUND: Electrophysiological endophenotypes are far less explored in bipolar disorder as compared to schizophrenia. No previous twin study of event-related potentials (ERPs) in bipolar illness has been reported. This study uses a twin design and advanced genetic model fitting analyses aiming to (1) assess and quantify the relationship of a range of ERP components with bipolar disorder with psychotic features, and (2) examine the source of the relationship (due to genetic or environmental factors). METHOD: P300, P50 suppression and mismatch negativity (MMN) were recorded in 10 discordant monozygotic (MZ) bipolar twin pairs, six concordant MZ bipolar twin pairs and 78 control twin pairs. Statistical analyses were based on structural equation modelling. RESULTS: Bipolar disorder was significantly associated with smaller P300 amplitude and decreased P50 suppression. Genetic correlations were the main source of the associations, estimated to be -0 x 33 for P300 amplitude and 0 x 46 for P50 ratio. Individual-specific environmental influences were not significant. MMN and P300 latency were not associated with the illness. CONCLUSIONS: The results provide supporting evidence that P300 amplitude and P50 suppression ratio are ERP endophenotypes for bipolar disorder.

Adult↗
PubMed2006

Linkage disequilibrium analysis of the CHRNA7 gene and its partially duplicated region in schizophrenia.

Several previous studies have reported a significant linkage between markers in the alpha 7 nicotinic cholinergic receptor subunit (CHRNA7) gene and either schizophrenia or the P50 sensory gating deficit, a schizophrenia endophenotype. However, CHRFAM7A, a partially duplicated gene 1.6Mb upstream of the CHRNA7 gene, has complicated further genetic analysis. We genotyped 14 polymorphic markers throughout the full-length CHRNA7 gene and the duplicated region in 188 unrelated Han Chinese patients with schizophrenia and 188 controls. The duplicated regions were assessed by genotyping up- and down-stream polymorphic markers in the vicinity of each region and analyzing the linkage disequilibrium (LD) between each pair of markers. No evidence of risk variants for schizophrenia in either the CHRNA7 gene or the partially duplicated region was found in the LD analysis. A significant deviation from the Hardy-Weinberg equilibrium (HWE) was found only in the genotypic distribution of SNP9 (IVS4-1912) in patients (p=0.00829), but not in controls. In conclusion, our LD analysis did not reveal any association between schizophrenia in our Han Chinese population and the CHRNA7 gene or its partially duplicated region. However, we could not exclude the possibility of a weak genetic effect due to the small sample size. Analyses of larger samples and higher-density markers, particularly around SNP9 (IVS4-1912), are still needed.

Asian People↗
PubMed2006

Heritability and reliability of P300, P50 and duration mismatch negativity.

BACKGROUND: Event-related potentials (ERPs) have been suggested as possible endophenotypes of schizophrenia. We investigated the test-retest reliabilities and heritabilities of three ERP components in healthy monozygotic and dizygotic twin pairs. METHODS: ERP components (P300, P50 and MMN) were recorded using a 19-channel electroencephalogram (EEG) in 40 healthy monozygotic twin pairs, 19 of them on two separate occasions, and 30 dizygotic twin pairs. Zygosity was determined using DNA genotyping. RESULTS: High reliabilities were found for the P300 amplitude and its latency, MMN amplitude, and P50 suppression ratio components. ICC=0.86 and 0.88 for the P300 amplitude and P300 latency respectively. Reliability of MMN peak amplitude and mean amplitude were 0.67 and 0.66 respectively. P50 T/C ratio reliability was 0.66. Model fitting analyses indicated a substantial heritability or familial component of variance for these ERP measures. Heritability estimates were 63 and 68% for MMN peak amplitude and mean amplitude respectively. For P50 T/C ratio, 68% heritability was estimated. P300 amplitude heritability was estimated at 69%, and while a significant familiality effect was found for P300 latency there was insufficient power to distinguish between shared environment and genetic factors. CONCLUSIONS: The high reliability and heritability of the P300 amplitude, MMN amplitude, and P50 suppression ratio components supports their use as candidate endophenotypes for psychiatric research.

Adult↗
PubMed2006

Genetics of disc degeneration.

Low back pain from degenerative disc disease (DDD) is one of the most common disorders seen in general and orthopaedic practices. DDD has been attributed to the accumulation of environmental factors, primarily mechanical insults and injuries, imposed on the "normal" aging changes. However, recent studies have shown an association between genetic influences and disc degeneration, with risk of developing DDD quoted to be increased up to six times that of the general population. It is likely that DDD is a complex, multifactorial disease determined by the interplay between gene(s) and the environment. This review focuses on the evidence for genetic disposition, the genes or biological processes that are implicated, and the need to consolidate resources and clarify phenotype definition to take advantage of the new technologies in genetic analysis to enhance our understanding of this condition.

Extracellular Matrix Proteins↗
PubMed2006

Genetic overlap between P300, P50, and duration mismatch negativity.

Mismatch Negativity (MMN), P300, and P50 suppression event-related potential (ERP) components measure intermediate stages of information processing but little is known of how they relate to each other genetically. The present study used multivariate genetic model fitting analytic techniques in 46 monozygotic and 32 dizygotic twin pairs. P300, P50 suppression, and MMN were recorded using a 19-channel electroencephalograph (EEG). Zygosity was determined using DNA genotyping. Little evidence for either genetic or environmental association between each of the three ERP paradigms was found. This result suggests that P300, MMN, and P50 suppression serve to evaluate different brain information processing functions that may be mediated by distinct neurobiological mechanisms which in turn are influenced by different sets of genes. Within paradigm, P300 amplitude and latency shared about half of their genetic effects.

Electroencephalography↗
PubMed2006

Cerebral asymmetry in 14 year olds born very preterm.

The normal pattern of cerebral asymmetry may be altered in neurodevelopmental disorders such as autism and schizophrenia. Babies born very preterm have an increased risk of brain damage, and brain abnormalities which persist into adolescence. This study aimed to ascertain whether preterm birth affects the development of fronto-occipital asymmetry. Structural MRI (magnetic resonance imaging) scans from 14 year old individuals born very preterm (n = 61; mean age 14 years 11 months; 29 male) and age-matched full-term controls (n = 49; mean age 14 years 11 months; 31 male) underwent morphometric analysis, using well-validated stereological methods. Measurements of right and left prefrontal, premotor, sensorimotor and occipitoparietal regional volumes were made and asymmetry indices calculated. These factors underwent a reductive factor analysis. There were no significant between-group differences in fronto-occipital asymmetry between the preterm adolescents and their full-term counterparts. It seems unlikely, therefore, that preterm birth per se deviates the development of normal fronto-occipital asymmetry. Neonatal periventricular haemorrhage with ventricular dilatation revealed by ultrasound may be associated with reversal of asymmetry in the sensorimotor area.

Adolescent↗
PubMed2006

Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population.

STUDY DESIGN: Large scale, case-control study. OBJECTIVE: To assess the effect of the Taq I alleles in vitamin D receptor on the risk of developing degenerative disc disease in a Southern Chinese population. SUMMARY OF BACKGROUND DATA: Previous studies in Finns and Japanese suggest that the Taq I polymorphism of vitamin D receptor is associated with the development of degenerative disc disease in the lumbar spine. However, sample sizes were small, and the results need to be confirmed in other populations. METHOD: Lumbar degenerative disc disease was defined by magnetic resonance imaging (MRI) on 804 Southern Chinese volunteers between 18 and 55 years of age. Restriction enzyme digestion of polymerase chain reaction products was used to analyze the Taq I alleles. The resulting genotypes were correlated with the presence of lumbar disc degeneration and bulge on MRI. RESULTS: Using logistic regression analysis and adjusting for age and sex, the t allele of Taq I in vitamin D receptor gene was significantly associated with degenerative disc disease, with an odds ratio (OR) of 2.61 (95% confidence interval [CI] 1.15-5.90, P = 0.041). Further subgroup analysis showed that in individuals younger than 40 years, the OR was even higher, at 5.97 (95% CI 1.69-21.15, P = 0.002). Similarly, disc bulge was significantly associated with t allele (OR = 7.17, 95% CI 1.43-36.01, P = 0.001) in individuals younger than 40 years. Anular tears and the Schmorl nodes were not associated with the t allele of Taq I polymorphism. CONCLUSION: To our knowledge, this is the largest scale genetics study to date using MRI to define precisely degenerative disc disease in the Southern Chinese population. We showed that the t allele of vitamin D receptor Taq I is associated with a high risk of degenerative disc disease and disc bulge developing, especially in individuals younger than 40 years.

Adolescent↗
PubMed2006

Design and analysis of association studies using pooled DNA from large twin samples.

Evidence is mounting that multiple genes are involved in complex traits and that these each account for very small proportions of the overall phenotypic variance. Association studies of many markers in 1000s of individuals will be required to identify such genes. A number of large twin cohorts have already been collected and provide a valuable resource for carrying out studies that are robust to the effect of population stratification. Technologies based on microarrays will soon allow 1.000,000 SNPs to be typed at one time, however financial considerations prevent most researchers from using these approaches to genotype all individuals. Recently, microarrays have been shown to give accurate allele frequency measurements in pooled DNA samples and provide a simple way to select the best markers for individual genotyping. This drastically reduces the cost and workload of large scale association studies. One limitation of this methodology relates to the analytical procedures which have only been developed to allow comparison of two pools e.g. case/control pools. In this paper we use meta-regression to analyze pooled DNA data allowing the allele frequency in each pool to be related to the average quantitative phenotypic measure of the individuals whose DNA were used to construct the pools. Alongside this we describe a technique that can be used to determine the power for such studies. We present results from some preliminary investigations of different pooling strategies that can be applied to large twin samples and demonstrate that the method retains a large proportion of the power available from individual genotyping.

Computer Simulation↗
PubMed2006

Intellectual asymmetry and genetic liability in first-degree relatives of probands with schizophrenia.

Intellectual asymmetry with superiority of verbal skills to spatial skills frequently characterises patients with schizophrenia, but it is unclear whether this pattern also reflects genetic susceptibility to the disorder. We examined the association of a continuous measure of genetic liability to schizophrenia with Verbal-Spatial Contrast IQ (an index of intellectual asymmetry) in 108 first-degree relatives without psychosis of probands with schizophrenia. Higher genetic liability was significantly associated with greater intellectual asymmetry in favour of verbal skills. Intellectual asymmetry with a relative superiority of verbal skills to spatial skills represents a putative endophenotype of schizophrenia.

Adolescent↗
PubMed2005

Whole genome linkage scan of recurrent depressive disorder from the depression network study.

Genome-wide linkage analysis was carried out in a sample of 497 sib pairs concordant for recurrent major depressive disorder (MDD). There was suggestive evidence for linkage on chromosome 1p36 where the LOD score for female-female pairs exceeded 3 (but reduced to 2.73 when corrected for multiple testing). The region includes a gene, MTHFR, that in previous studies has been associated with depressive symptoms. Two other regions, on chromosomes 12q23.3-q24.11 and 13q31.1-q31.3, showed evidence for linkage with a nominal P < 0.01. The 12q peak overlaps with a region previously implicated by linkage studies of unipolar and bipolar disorders and contains a gene, DAO, that has been associated with both bipolar disorder and schizophrenia. The 13q peak lies within a region previously linked strongly to panic disorder. A fourth modest peak with an LOD of greater than 1 on chromosome 15q lies within a region that showed genome-wide significant evidence of a recurrent depression locus in a previous sib-pair study. Both the 12q and the 15q findings remained significant at genome-wide level when the data from the present study and the previous reports were combined.

Adolescent↗
PubMed2005

An association analysis of microsatellite markers across the Prader-Willi/Angelman critical region on chromosome 15 (q11-13) and autism spectrum disorder.

Autism (OMIM 209850) is a neurodevelopmental disorder with a significant genetic component of a complex nature. Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region (PWACR) on chromosome 15 (q11-13) have been described in several individuals with autism. We have examined five microsatellite markers spread across the 4 Mb PWACR for linkage disequilibrium (LD) in 148 families with autism spectrum disorder (ASD) and a subset of 82 families with autism using the extended transmission disequilibrium test (ETDT). The markers examined were D15S11, D15S128, D15S1506, GABRB3, and D15S1002. In addition we have examined the microsatellite D15S822 for hemizygous deletion status in our sample as it had been previously reported to be increased in autism. We found no significant LD with any of the markers tested either in the ASD or autism families when looking at paternal and maternal meioses combined. However, as there are known imprinted genes in the region, including possibly GABRB3, we also examined for LD in paternal and maternal meioses separately. Examining paternal transmissions only, we found marginal evidence for LD with a protective allele at marker D15S11 in the ASD families (Chi-sq 7 df, P = 0.05) and marginal evidence for risk alleles at markers D15S1506 (Chi-sq 13.7, 6 df, P = 0.06), GABRB3 (Chi-sq 15.9, 8 df, P = 0.11) and D15S1002 (Chi-sq 17.7, 9 df, P = 0.08) in the autism only families. The allele responsible for the association with GABRB3 is the 191 allele which was previously reported to be overtransmitted. Hemizygous deletion of the microsatellite D15S822 was found in 3 out of 340 independent chromosomes in our sample; a rate of 0.8%. This is not significantly different to the frequency in the general population. In conclusion, our results did not rule out the involvement of this chromosomal region, but provided further evidence, albeit very limited, to implicate GABRB3. Further more systematic work in larger samples is required and confirmation that GABRB3 is imprinted is desirable.

Alleles↗
PubMed2005

Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961.

CONTEXT: Schizophrenia is a common major mental disorder. Intrauterine nutritional deficiency may increase the risk of schizophrenia. The main evidence comes from studies of the 1944-1945 Dutch Hunger Winter when a sharp and time-limited decline in food intake occurred. The most exposed cohort conceived during the famine showed a 2-fold increased risk of schizophrenia. OBJECTIVE: To determine whether those who endured a massive 1959-1961 famine in China experienced similar results. DESIGN, SETTING, AND PARTICIPANTS: The risk of schizophrenia was examined in the Wuhu region of Anhui, one of the most affected provinces. Rates were compared among those born before, during, and after the famine years. Wuhu and its surrounding 6 counties are served by a single psychiatric hospital. All psychiatric case records for the years 1971 through 2001 were examined, and clinical and sociodemographic information on patients with schizophrenia was extracted by researchers who were blinded to the nature of exposure. Data on number of births and deaths in the famine years were available, and cumulative mortality was estimated from later demographic surveys. MAIN OUTCOME MEASURES: Evidence of famine was verified, and unadjusted and mortality-adjusted relative risks of schizophrenia were calculated. RESULTS: The birth rates (per 1000) in Anhui decreased approximately 80% during the famine years from 28.28 in 1958 and 20.97 in 1959 to 8.61 in 1960 and 11.06 in 1961. Among births that occurred during the famine years, the adjusted risk of developing schizophrenia in later life increased significantly, from 0.84% in 1959 to 2.15% in 1960 and 1.81% in 1961. The mortality-adjusted relative risk was 2.30 (95% confidence interval, 1.99-2.65) for those born in 1960 and 1.93 (95% confidence interval, 1.68-2.23) for those born in 1961. CONCLUSION: Our findings replicate the Dutch data for a separate racial group and show that prenatal exposure to famine increases risk of schizophrenia in later life.

Adult↗
PubMed2005

The serotonin transporter gene as a QTL for ADHD.

Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD.

Adolescent↗
PubMed2005

DNA pooling analysis of 21 norepinephrine transporter gene SNPs with attention deficit hyperactivity disorder: no evidence for association.

The norepinephrine system is known to play a role in attentional and cognitive-energetic mechanisms and is thought to be important in attention deficit hyperactivity disorder (ADHD). Stimulant medications are known to alter the activity of norepinephrine as well as dopamine in the synapse and the highly selective norepinephrine reuptake inhibitor, atomoxetine, is an effective treatment for ADHD symptoms. This study set out to investigate whether common polymorphisms within the norepinephrine transporter gene (NET1) are associated with DSM-IV ADHD combined subtype, using a sample that has previously shown association with genes that affect the synaptic release and uptake of neurotransmitters; DAT1 and SNAP-25. We identified 21 single nucleotide polymorphisms (SNPs) from publicly available databases that had minor allele frequencies > or =5% and span the NET1 genomic region, including those analyzed in previous studies of ADHD. DNA pooling was used to screen for associations using two case pools (n = 180 cases) and four control pools (n = 334 controls). We identified three SNPs that showed suggestive evidence for association using either case-control or within family tests of association, however, none of these were significant after adjustment for the number of markers analyzed. We conclude that none of the markers show significant evidence of association with ADHD although we cannot rule out small genetic effects.

Algorithms↗
PubMed2005

Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B.

It has been widely postulated that the categorical diagnosis of attention deficit hyperactivity disorder (ADHD) should be seen as the extreme end of a set of traits quantitatively distributed in the general population. A consequence of this is that the genes associated with DSM-IV ADHD should also influence these underlying traits in non-affected individuals. The aim of this study was to examine if specific candidate loci previously shown to be associated with DSM-IV ADHD, also act as quantitative trait loci (QTLs) for ADHD-symptoms in the general population. We have genotyped five candidate markers in a population-based sample of male dizygous twin-pairs (n = 329 pairs). We found little evidence to support a role for the previously-nominated alleles of a DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near to DRD5, in the distribution of ADHD-symptoms scores; however, we found some evidence to suggest that the DAT1 3'UTR VNTR and weak evidence that a microsatellite in SNAP-25 may have a role in continuous measures of ADHD-symptoms hyperactivity above and beyond their role in clinical ADHD.

Alleles↗
PubMed2005

Sense of hyper-positive self and response to cognitive therapy in bipolar disorder.

INTRODUCTION: Cognitive therapy (CT) for bipolar disorder emphasizes the monitoring and regulation of mood, thoughts and behaviour. The Sense of Hyper-Positive Self Scale (SHPSS) measures the extent to which bipolar patients value themselves and perceive themselves to possess personal attributes (e.g. dynamism, persuasiveness and productiveness) associated with a state of being 'mildly high', which does not reach the severity of clinical hypomania. It is hypothesized that patients who score highly on the SHPSS do not respond well to cognitive therapy. METHOD: One hundred and three bipolar-I patients were randomized into CT and control groups. The SHPSS was administered at baseline and at a 6-month follow-up. RESULT: The SHPSS had good test-retest reliability after 6 months. At baseline, the Goal-Attainment Dysfunctional Attitudes contributed significantly to the SHPSS scores after the mood measures were controlled for in a regression analysis. There was a significant interaction between baseline SHPSS scores and group allocation in predicting relapse during therapy. Patients who scored highly on the SHPSS had a significantly increased chance of relapse after controlling for mood scores, levels of social functioning at recruitment, and the previous number of bipolar episodes. CONCLUSION: Not all patients benefited from CT. For patients with high SHPSS scores, CT was less efficacious. The results also indicate that future studies could evaluate targeting these attributes and dysfunctional beliefs with intensive cognitive behavioural techniques.

Achievement↗
PubMed2005

A behavioural genomic analysis of DNA markers associated with general cognitive ability in 7-year-olds.

BACKGROUND: Five DNA markers (single-nucleotide polymorphisms, SNPs) have recently been found to be associated with general cognitive ability ('g') in a sample of 7414 7-year-old twins. These children have also been studied at 2, 3, 4, and 7 years of age on measures of cognitive and language development and behaviour problems; family environment was also assessed. METHODS: We used these data to conduct a behavioural genomic analysis of the five SNPs and a composite of them ('SNP set') that explored developmental, multivariate, and genotype-environment (GE) issues. RESULTS: The 'g' SNP set identified at 7 years yielded significant associations with 'g' as early as 2 years. In multivariate analyses at 7 years, the 'g' SNP set was more strongly associated with verbal than nonverbal ability and with reading more than mathematics performance. GE correlations were found between the SNP set for 'g' at 7 years and preschool proximal measures of the family environment (chaos and discipline) rather than distal measures (maternal education and father's occupational class), suggesting evocative rather than passive GE correlation. Significant GE interactions were found for discipline, education and occupation in which the association between the SNP set and 'g' at 7 years is stronger in low-risk environments. CONCLUSIONS: Although the effect sizes of the five SNP associations are very small, behavioural genomic analyses using a 'g' SNP set illustrate how developmental, multivariate and GE questions can be addressed as more DNA associations are identified for complex traits such as 'g'.

Child↗