Huaqing Meng

Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population

Haploinsufficiency for or mutation in at least one gene from the velocardiofacial syndrome (VCFS) region at chromosome 22q11 is implicated in psychosis. Linkage disequilibrium mapping of the region in patients identified a segment containing two genes, proline dehydrogenase (PRODH) and DGCR6, as candidates [Liu et al., 2002a ] and by analysis of additional polymorphisms the PRODH gene was associated with schizophrenia in adult and early onset patients. In the present study we provide additional evidence in support of genetic association between PRODH and schizophrenia in a Chinese population. We analyzed the PRODH gene in a samples of schizophrenic patients and their families from Sichuan, SW China consisting of 528 family trios and sibling pairs. We genotyped six SNPs, PRODH*1195C → T, PRODH*1482C → T, PRODH*1483A → G, PRODH*1766A → G, PRODH*1852G → A PRODH*1945T → C, two of which (PRODH*1483A → G and PRODH*1852G → A) have not been previously reported. We found association with schizophrenia for two haplotypes consisting of PRODH*1945T → C and PRODH*1852G → A (Global P = 0.006), and PRODH*1852G → A and PRODH*1766A → G (Global P = 0.01) which include one of the newly identified markers. After six‐fold Bonferroni correction for multiple testing the PRODH*1945T‐C/PRODH*1852G‐A haplotypes remained significant. This is a sub‐haplotype of the PRODH haplotype previously associated with schizophrenia and it also maps to the 3′ region of the gene, indicating that this is the region most likely to contain the underlying risk alleles. Overall this finding supports a role for the PRODH locus in schizophrenia.

Neurocognitive deficits in first-episode schizophrenic patients and their first-degree relatives

Some neuropsychological abilities, particularly those affecting memory, attention and executive function, are impaired amongst both schizophrenic patients and their unaffected relatives, implying that these deficits are at least partly genetic in origin. However neuropsychological performance can be altered by medication, and has rarely been examined in first onset, drug naive patients. The objective of this study was to determine whether selected neurocognitive abilities are impaired in first‐onset schizophrenic patients and their relatives compared to controls. We examined attention and speed of information processing, memory and learning, verbal function, visuoconstructive abilities and executive function in 207 first‐episode schizophrenic patients (163 of whom were drug naïve), 322 of their first‐degree relatives and 133 unrelated normal controls. The data were subjected to multilevel modeling to compare neurocognitive performance between schizophrenic probands, relatives and controls while taking into account potential correlations among members of the same family; age, gender, and years of education were included as covariates. Of the three groups, schizophrenic patients performed poorest at all neuropsychological tests, suggestive of a broad range of neurocognitive deficits. Their first‐degree relatives showed a narrower pattern of poor performance at Digit Symbol, Digit Span, Trail Making, Verbal Fluency test, Tower of Hanoi, and WCST‐M tests. Our findings show that selected neurocognitive deficits especially attention and executive function are impaired in the families of schizophrenic patients. These patterns of neurocognitive deficits may represent “endophenotypes” denoting varying degrees of vulnerability to schizophrenia and may be of value in future molecular genetic studies.

Identifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations

The dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP ‘A’) in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia.

Association analysis of the RGS4 gene in Han Chinese and Scottish populations with schizophrenia

We investigated the RGS4 as a susceptibility gene for schizophrenia in Chinese Han (184 trios and 138 sibling pairs, a total of 322 families) and Scottish (580 cases and 620 controls) populations using both a family trio and case‐control design. Both the samples had statistical power greater than 70% to detect a heterozygote genotype relative risk of >1.2 for frequent RGS4‐risk alleles. We genotyped four single nucleotide polymorphisms (SNPs) which have previously been associated with schizophrenia as either individually or part of haplotypes. Allele frequencies and linkage disequilibrium between the SNPs was similar in the two populations. In the Chinese sample, no individual SNPs or any of their haplotypes were associated with schizophrenia. In the Scottish population, one SNP (SNP7) was significantly over‐represented in the cases compared with the controls (0.44 vs. 0.38; A allele; χ2 7.08, P = 0.011 after correction for correlation between markers by permutation testing). One two‐marker haplotype, composed of alleles T and A of SNP4 and SNP7, respectively, showed individual significance after correction by permutation testing (χ2 6.8; P = 0.04). None of the full four‐marker haplotypes showed association, including the G‐G‐G‐G haplotype previously associated with schizophrenia in more than one sample and the A‐T‐A‐A haplotype. Thus, our data do not directly replicate previous associations of RGS4, but association with SNP 7 in the Scottish population provides some support for a role in schizophrenia susceptibility. We cannot conclusively exclude RGS4, as associated haplotypes are likely to be surrogates for unknown causative alleles, whose relationship with overlying haplotypes may differ between the population groups. Differences in the association seen across the two populations could result from methodological factors such as diagnostic differences but most likely result from ethnic differences in haplotype structures within RGS4.

Premorbid tobacco smoking is associated with later age at onset in schizophrenia.

Rates of cigarette smoking in individuals with schizophrenia well exceed those in the general population and in other mental illnesses. In the present study, we examined the relationship between smoking status, clinical characteristics and cognitive functions in 230 male Chinese schizophrenia patients. They were interviewed by experienced psychiatrists using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (SCID-P). Clinical symptoms were rated using the Positive and Negative Syndrome Scale (PANSS), and the Revised Tolerance Questionnaire (RTQ) used to evaluate the severity of nicotine dependence. Nine neuropsychological tests were used to assess cognitive function. We found that never-smokers had a younger age at examination and earlier onset and longer duration of illness than smokers and ex-smokers. The age of initiation of regular smoking in patients was significantly earlier than their age of illness onset. We found that longer duration of illness was significantly associated with higher RTQ scores. Ex-smokers with schizophrenia performed significantly more poorly on the Stroop C test than smokers. The results imply that smoking may affect cognitive function and illness onset time in patients with schizophrenia.

Genetic influences on resting‐state functional networks: A twin study

Alterations in resting‐state networks (RSNs) are often associated with psychiatric and neurologic disorders. Given this critical linkage, it has been hypothesized that RSNs can potentially be used as endophenotypes for brain diseases. To validate this notion, a critical step is to show that RSNs exhibit heritability. However, the investigation of the genetic basis of RSNs has only been attempted in the default‐mode network at the region‐of‐interest level, while the genetic control on other RSNs has not been determined yet. Here, we examined the genetic and environmental influences on eight well‐characterized RSNs using a twin design. Resting‐state functional magnetic resonance imaging data in 56 pairs of twins were collected. The genetic and environmental effects on each RSN were estimated by fitting the functional connectivity covariance of each voxel in the RSN to the classic ACE twin model. The data showed that although environmental effects accounted for the majority of variance in wide‐spread areas, there were specific brain sites that showed significant genetic control for individual RSNs. These results suggest that part of the human brain functional connectome is shaped by genomic constraints. Importantly, this information can be useful for bridging genetic analysis and network‐level assessment of brain disorders. Hum Brain Mapp 36:3959–3972, 2015.

Fronto-limbic disconnection in depressed patients with suicidal ideation: A resting-state functional connectivity study

BACKGROUND Suicidal ideation (SI) is highly prevalent and a known symptom of Major Depressive Disorder (MDD), but its underlying biological mechanisms are relatively unknown. Several studies linked suicidal ideation to dysfunctional brain circuits, specifically fronto-limbic connections. The purpose of this work was to investigate fronto-limbic disconnection in MDD patients with or without SI. METHODS MDD patients with SI (SI, n=28) or without SI (NSI, n=20), identified by the Scale for Suicide Ideation and healthy controls (HCs, n=30) underwent resting-state functional MRI scanning. The functional properties of correlations in neural activity (intrinsic functional connectivity, iFC) of the rostral anterior cingulate cortex (rACC) were analyzed among the three groups. Furthermore, correlation analyses between iFC, SI severity and depression severity were performed. RESULTS We found that the SI group exhibited decreased iFC between the rACC, the orbitomedial prefrontal cortex and the right middle temporal pole compared to HCs and NSI groups. The NSI group showed decreased iFC between the rACC and the orbitomedial prefrontal cortex compared to HCs. In the SI group, iFC strength between the right rACC and the middle temporal pole positively correlated with SI severity. CONCLUSION Transdiagnostic and diagnosis-specific alterations of fronto-limbic iFC were found in MDD patients with or without SI. Disrupted fronto-limbic circuits may impact decision-making and emotional processing in SI. These results provide useful information about the pathophysiological mechanisms of MDD patients with SI.

Antidepressant Effects of Electroconvulsive Therapy Correlate With Subgenual Anterior Cingulate Activity and Connectivity in Depression.

AbstractThe mechanisms underlying the effects of electroconvulsive therapy (ECT) in major depressive disorder (MDD) are not fully understood. Resting-state functional magnetic resonance imaging (rs-fMRI) is a new tool to study the effects of brain stimulation interventions, particularly ECT. The authors aim to investigate the mechanisms of ECT in MDD by rs-fMRI.They used rs-fMRI to measure functional changes in the brain of first-episode, treatment-naive MDD patients (n = 23) immediately before and then following 8 ECT sessions (brief-pulse square-wave apparatus, bitemporal). They also computed voxel-wise amplitude of low-frequency fluctuation (ALFF) as a measure of regional brain activity and selected the left subgenual anterior cingulate cortex (sgACC) to evaluate functional connectivity between the sgACC and other brain regions.Increased regional brain activity measured by ALFF mainly in the left sgACC following ECT. Functional connectivity of the left sgACC increased in the ipsilateral parahippocampal gyrus, pregenual ACC, contralateral middle temporal pole, and orbitofrontal cortex. Importantly, reduction in depressive symptoms were negatively correlated with increased ALFF in the left sgACC and left hippocampus, and with distant functional connectivity between the left sgACC and contralateral middle temporal pole. That is, across subjects, as depression improved, regional brain activity in sgACC and its functional connectivity increased in the brain.Eight ECT sessions in MDD patients modulated activity in the sgACC and its networks. The antidepressant effects of ECT were negatively correlated with sgACC brain activity and connectivity. These findings suggest that sgACC-associated prefrontal-limbic structures are associated with the therapeutic effects of ECT in MDD.

PRODH gene is associated with executive function in schizophrenic families

The aim of this study was to investigate the relationship between polymorphisms in the PRODH and COMT genes and selected neurocognitive functions. Six SNPs in PRODH and two SNPs in COMT were genotyped in 167 first‐episode schizophrenic families who had been assessed by a set of 14 neuropsychological tests. Neuropsychological measures were selected as quantitative traits for association analysis. The haplotype of SNPs PRODH 1945T/C and PRODH 1852G/A was associated with impaired performance on the Tower of Hanoi, a problem‐solving task mainly reflecting planning capacity. There was no significant evidence for association with any other neuropsychological traits for other SNPs or haplotypes of paired SNPs in the two genes. This study takes previous findings of association between PRODH and schizophrenia further by associating variation within the gene with performance on a neurocognitive trait characteristic of the illness. It fails to confirm previous reports of an association between COMT and cognitive function.

The functional MMP-9 microsatellite marker is not associated with episodic memory in humans

Division of Psychological Medicine and SGDP Centre, Institute of Psychiatry, King’s College, London, UK, Psychiatric Laboratory and Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Department of Psychiatry, University of Hong Kong, Hong Kong, Department of Psychiatry, Chongqing University of Medical Science, Chongqing, China and Unit of Clinical Medicine, Department of Clinical Morphological and Technological Sciences, University of Trieste, Trieste, Italy Correspondence to Dr Tao Li, MD, PhD, Institute of Psychiatry, Box P082, De Crespigny Park, Denmark Hill, London, UK, SE5 8AF Tel: + 44 20 7848 0631; e-mail: tao.li@iop.kcl.ac.uk