Jinbo Fan

Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 × 10−9) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 × 10−8, rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Whole-genome association study of bipolar disorder

We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372 193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 × 10−7) and tetraspanin-8 (TSPAN8; P=6.11 × 10−7). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 × 10−8, TSPAN8; P=7.57 × 10−7 and EGFR; P=8.36 × 10−8). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case–control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case–Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia : a large-scale association study plus meta-analysis

BACKGROUND A common functional polymorphism (Val/Met) in the catechol-O-methyltransferase gene (COMT) that markedly affects enzyme activity has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans. It is hypothesized that the high activity Val allele slightly increases risk for schizophrenia through its effect on dopamine-mediated prefrontal information processing. METHODS We compared the allele/genotype frequencies of the Val/Met polymorphism in a large independent patient-control sample (862 patient and 928 healthy control subjects) from Han Chinese population, and an update meta-analysis was performed to assess the collective evidence across individual studies. RESULTS No statistically significant differences were found in allele or genotype frequencies between patient and normal control subjects, although a nonsignificant overrepresentation of the Val allele in schizophrenia patients (odds ratio [OR] = 1.09, 95% confidence interval [CI] = .94-1.26) was suggested. Comparatively, the meta-analysis of all published population-based association studies showed statistically significant evidence for heterogeneity among the group of studies. Stratification of the studies by ethnicity of the samples yielded no significant evidence for an association with the Val allele in Asian population (OR = .96, 95% CI = .85-1.09), nor in European population (OR = 1.06, 95% CI = .95-1.19). CONCLUSIONS Our data provide minimal evidence that the Val allele is a susceptibility factor for schizophrenia in either European or Asian populations.

Family-based association study of DTNBP1 in 6p22.3 and schizophrenia

P1328 (rs742105) T C T C C P1655 (rs2619539) G G C C C P1763 (rs2619522) T T T T G P1578 (rs1018381) C C C C T P1583 (rs909706) A A G G G Estimated probability 0.37 0.26 0.12 0.1 0.05 O 183.83 115.31 60.16 41.67 22.08 E 166.69 116.46 55.57 46.72 22.89 Var(O E) 47.17 42.84 23.45 18.37 11.04 w (1 df) 6.22 0.03 0.90 1.39 0.06 P-value 0.01 0.86 0.34 0.24 0.81 Global P-value 0.00072 Molecular Psychiatry (2003) 8, 1008 & 2003 Nature Publishing Group All rights reserved 1359-4184/03

Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia

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Family-Based Association Study of Lithium-Related and Other Candidate Genes in Bipolar Disorder

The serotonin transporter gene (SLC6A4) is a candidate gene for schizophrenia based on serotonin transporters crucial role in serotonergic neurotransmission. However, association studies have produced conflicting results regarding the association between two common SLC6A4 gene polymorphisms, the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR) polymorphisms, and schizophrenia susceptibility. To further elucidate the putative association between the two SLC6A4 gene polymorphisms and schizophrenia susceptibility, we performed a meta-analysis based on all original published association studies between schizophrenia and the 5-HTTLPR and STin2 VNTR polymorphisms published before April 2004. Our analyses showed no statistically significant evidence for the association between the Short allele of the 5-HTTLPR polymorphism and schizophrenia (random-effects pooled odds ratio (OR)=0.99, 95% Confidence Interval (CI)=0.92–1.07, Z=−0.23, P=0.82) from 19 population-based association studies consisting of 2990 case and 3875 control subjects. However, highly significant evidence for association between the STin2.12 allele of the STin2 VNTR polymorphism (random-effects pooled OR=1.24, 95% CI=1.11–1.38, Z=3.82, P=0.00014) and schizophrenia was found from 12 population-based association studies consisting of 2177 cases and 2369 control subjects. Our meta-analysis suggests that the STin2.12 allele of the STin2 VNTR polymorphism is likely a risk factor for schizophrenia susceptibility. Our data imply that following completion of the International HapMap Project, a comprehensive evaluation of a set of markers that fully characterize the linkage disequilibrium relationships at the SLC6A4 gene should be tested in large well-characterized clinical samples in order to understand the role of this gene in schizophrenia susceptibility.

A family-based association study of T1945C polymorphism in the proline dehydrogenase gene and schizophrenia in the Chinese population

CONTEXT Association studies in bipolar disorder have been focused on a relatively narrow pool of candidate genes based on a limited understanding of the underlying pathophysiologic features. Recent developments suggest that a broader pool of genes may be associated with this disorder. OBJECTIVE To examine the association between genes related to the lithium mechanism of action, as well as other positional and functional candidates, with bipolar I disorder. DESIGN We examined a dense set of haplotype-tagging single-nucleotide polymorphisms using a gene-based test of association. PARTICIPANTS Three hundred seventy-nine parent-affected offspring trios. RESULTS No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and gamma-aminobutyric acid(A) beta2 receptor subunit (GABRB2) yielded evidence of association (empirical P value, <.005). Among 3 genes associated with schizophrenia or bipolar disorder in multiple previous studies, including dysbindin (DTNBP1), neuregulin (NRG1), and disrupted-in-schizophrenia 1 (DISC1), only DISC1 showed evidence of association in this cohort. In a secondary analysis of these 6 genes among parent-proband trios with a history of psychosis, evidence of the association with SIAT4A was strengthened. CONCLUSIONS These results suggest novel candidates and 1 gene (DISC1) previously associated with schizophrenia that merit further study in bipolar disorder. However, polymorphisms in major lithium-signaling genes do not appear to contribute substantially to bipolar liability.

Family-based association studies of COMT gene polymorphisms and schizophrenia in the Chinese population.

Previous studies have reported genetic linkage evidence for a candidate gene of schizophrenia on chromosome 22q11 but no genes in this region have been really confirmed to be involved in the etiology of schizophrenia so far. Very recently, the proline dehydrogenase gene (PRODH), located in the most centromeric part of the 22q11 microdeletion region, has been reported to be strongly associated with schizophrenia from three sets of independent samples and the most significant evidence for association was derived from a single nucleotide polymorphism-PRODH*1945(T/C). We genotyped this polymorphism in 166 Chinese family trios with schizophrenia from East China. No evidence for preferential transmission of the PRODH*1945 alleles from parents to affected offsprings was found using either Transmission Disequilibrium Test (P=0.4) or Haplotype-based Haplotype Relative Risk analysis (P=0.35). Our results suggest that the 1945(T/C) polymorphism of the proline dehydrogenase gene is unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.

Apolipoprotein E is a genetic risk factor for fetal iodine deficiency disorder in China

Family-based association studies of COMT gene polymorphisms and schizophrenia in the Chinese population

Linkage disequilibrium mapping of the chromosome 6q21–22.31 bipolar I disorder susceptibility locus†‡

Fetal iodine deficiency disorder (FIDD) is the principal form of endemic cretinism, and the most common cause of preventable mental deficiency in the world. However not everyone at risk develops FIDD and familial aggregation is common. This suggests that genetic factors may also be involved. The Apolipoprotein E (APOE) gene encodes for a lipoprotein that possesses a thyroid hormone binding domain, and APOE genotype may affect the efficiency with which thyroid hormone influences neuronal cell growth during the first and second trimesters of fetal development. We have compared ApoE genotypes in 91 FIDD cases with 154 local control subjects, recruited from three iodine deficiency areas in central China. We have also genotyped 42 FIDD family cases and 158 normal individuals from the families of local controls, and 375 population controls from Shanghai. APOE ε4 genotypes were significantly enriched in FIDD probands from each of the three iodine deficiency areas; the ε4 allele frequency was 16% vs 6% in controls. The same effect was also observed when we compared FIDD family cases with controls and control families. Our data suggest that in iodine-deficient areas, the APOE ε4 allele is a genetic risk factor for FIDD. The phenomenon may affect population selection and contribute to the low frequency of the ε4 allele in Chinese compared to Caucasian populations.