Sajid A. Shaikh

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (χ2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.

Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder

Brain‐derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant‐like effects in animals. BDNF gene polymorphisms have been associated with bipolar disorder. We tested two genetic polymorphisms of BDNF for their association with childhood‐onset mood disorders (COMD) within the context of a case‐control design. Two BDNF polymorphisms, a dinucleotide repeat (GT)n, and a single nucleotide polymorphism (SNP) in the coding region, val66met, were genotyped in 99 adults with a history of COMD and matched psychiatrically healthy controls. A genomic control (GC) method was used to evaluate population substructure. Alleles at (GT)n were highly associated with COMD in this sample (χ2 = 17.8; d.f. = 5; P = 0.0032). The odds of carrying the 168 bp allele were 3.94 times greater for cases than controls (CI = 1.72–9.04). Alleles of val66met were not significantly associated with COMD. GC analysis suggested population substructure was not a confounder of association. Analysis of haplotypes, in which (GT)n was treated as a binary variable (long vs. short alleles), provided significant evidence that the haplotype val/short contributes to liability to COMD. The BDNF (GT)n marker and the val/short haplotype are associated with COMD in this sample, in accordance with the previously described neurotrophic hypothesis of depression and some previous studies of association for bipolar disorder and neuroticism. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148‐7299:1/suppmat/index.html.

The Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Prediction of Neural Risk for Alzheimer Disease

CONTEXT The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may predict the risk of Alzheimer disease (AD). However, genetic association studies of the BDNF gene with AD have produced equivocal results. Imaging-genetics strategies may clarify the manner in which BDNF gene variation predicts the risk of AD via characterization of its effects on at-risk structures or neural networks susceptible in this disorder. OBJECTIVE To determine whether the BDNF Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to AD by examining (1) cortical thickness, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance. DESIGN A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan. SETTING University hospital. PARTICIPANTS A total of 69 healthy volunteers ranging from 19 to 82 years of age. MAIN OUTCOME MEASURES The BDNF Val66Met genotype, apolipoprotein E genotype, cortical thickness, microstructural integrity of white matter tracts, and episodic memory performance were evaluated. RESULTS The BDNF Val66Met polymorphism interacted with age to predict (1) cortical thickness (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility. CONCLUSIONS The BDNF gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a BDNF genetic mechanism of susceptibility in an intermediate phenotype related to AD.

The brain-derived neurotrophic factor gene in suicidal behaviour: a meta-analysis

Suicide is a prominent public health problem. Its aetiology is complex, and the brain-derived neurotrophic factor (BDNF) has been implicated. We performed the first meta-analysis of the functional BDNF marker Val⁶⁶Met (rs6265, 196G>A) in suicidal behaviour using data from 11 previously published samples plus our present sample (total n=3352 subjects, 1202 with history of suicidal behaviour. The meta-analysis including all 12 studies showed a trend for the Met-carrying genotypes and Met allele conferring risk for suicide (random-effects model p=0.096; ORMet-carrier=1.13, 95% CI 0.98-1.30, and random-effects model p=0.032; ORMet=1.16, 95% CI 1.01-1.32, respectively). Furthermore, we found the Met allele and the Met allele-carrying genotypes to be associated with history of suicide attempt (eight studies; allelic meta-analysis--random-effects model: p=0.013; fixed-effects model: p=0.006; genotypic meta-analysis--random-effects model: p=0.017; fixed-effects model: p=0.008). Taken together, the results from our study suggest that BDNF Val⁶⁶Met is involved in suicidality. Further studies are required to elucidate its role in suicidal behaviour.

Association of polymorphisms in the BDNF, DRD1 and DRD3 genes with tobacco smoking in schizophrenia

Emerging evidence indicates that the DRD1‐BDNF‐DRD3 cluster plays an important role in nicotine addiction. We have performed an association analysis of 42 SNPs within these genes with cigarette consumption in a group of 341 schizophrenia patients. The ACCG haplotype consisting of four BDNF markers (Val66Met (rs6265), rs11030104, rs2049045 and rs7103411) showed an association with the risk of smoking (p = 0.0002). Both DRD1 markers tested (rs4532 and rs686) and the DRD3 marker (rs1025398) showed association with quantity of tobacco smoked (p = 0.01, 0.005 and 0.002, respectively). Our findings are preliminary; however, they support the involvement of the DRD1, BDNF and DRD3 genes in smoking behaviour.

Association analyses of the DAOA/G30 and D-amino-acid oxidase genes in schizophrenia: further evidence for a role in schizophrenia.

A number of linkage studies have previously implicated the region of chromosome 13q34 in schizophrenia. Chumakov and colleagues (2002) identified a gene complex called G72 (now termed d-amino acid oxidase activator: DAOA)/G30 in this region and performed association analyses of the DAOA/G30 as well as the d-amino-acid oxidase (DAAO) gene with schizophrenia. DAAO oxidizes d-serine, a potent activator of the N-methyl-d-aspartate (NMDA) type glutamate receptor in the human brain whereas the DAOA protein is considered an activator of DAAO. The interaction of these two genes has thus been implicated in the NMDA receptor regulation pathway in schizophrenia. To date, several studies have shown a relatively consistent positive association between schizophrenia and DAOA/G30, but not with DAAO. The aim of our study was to further evaluate the contributions of these genes to the susceptibility to schizophrenia using two different sample sets. Our sample consisted of 168 matched case-control pairs as well as a family-based sample (n=113) for transmission disequilibrium test. Significant associations between the DAOA/G30 M-7 and M-18 polymorphisms and schizophrenia were observed in our case-control sample whereas no associations were observed for DAAO markers. We also observed significant or suggestive transmission disequilibrium for DAOA/G30 M-7, M-23, and M-24 to probands with schizophrenia in our family-based sample. Subsequent analysis of haplotypes made up of four DAOA/G30 markers, one marker selected from each of two linkage disequilibrium blocks that were observed in our sample as well as both ends (M-7 and M-25), were also associated with schizophrenia. Our data provide further evidence that the DAOA/G30 locus may play a role in the pathophysiology of schizophrenia. Although no direct link to genetic polymorphism in these genes and NMDA receptor function has been revealed, the present findings support previous reports implicating DAOA/G30 as susceptibility genes for schizophrenia. Further research is warranted to determine the functional variation underlying these findings and to relate this to the pathophysiology of schizophrenia.

BDNF and COMT polymorphisms: relation to memory phenotypes in young adults with childhood-onset mood disorder.

Recent investigations in several species have suggested a role for brain-derived neurotrophic factor (BDNF) in memory, which may be mediated by the influence of BDNF on neuronal plasticity in the hippocampus. BDNF polymorphisms have also been associated with mood disorders. Catechol-O-methyltransferase (COMT) metabolizes dopamine and has been implicated in prefrontal function, another area of the brain relevant for memory. In a sample of 63 young adults with a history of childhood-onset mood disorder, we typed three BDNF polymorphisms, including the BDNF Val66Met single nucleotide polymorphism (SNP), and the COMT Val108/158Met SNP. Multivariate analysis of variance was used to test the association between BDNF and COMT markers and measures of declarative memory. Variants at the three BDNF markers and one COMT marker were not associated with declarative memory function—p-values ranged from 0.25 to 0.98. Higher IQ (F=6.18, df=4, 58, p=0.0003) and female gender (F=4.41, df=4, 58, p=0.0035) were associated with more optimal performance on the memory tasks. This study did not provide evidence supporting an association between BDNF and COMT genes and declarative memory phenotypes.

Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain.

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1–DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients.

ANK3, CACNA1C and ZNF804A gene variants in bipolar disorders and psychosis subphenotype

Abstract Objectives. The ANK3, CACNA1C and ZNF804A genes have been implicated in both bipolar disorders (BPD) and schizophrenia (SCZ). It has been suggested that BPD with psychosis may be a clinical manifestation of genes overlapping between BPD and SCZ. We therefore tested the association of these genes with BPD in a large family-based sample, and then dissected the phenotype into psychosis present or absent subgroups. Methods. We genotyped four high interest single nucleotide polymorphisms from ANK3 (rs10994336, rs9804190), CACNA1C (rs1006737), and ZNF804A (rs1344706). Family based association testing (FBAT) was performed on 312 families, and within psychotic (N = 158) and non-psychotic BPD (N = 119) subgroups. Results. In the whole sample, we found a nominal association in ZNF804A (rs1344706, P = 0.046), and a trend in CACNA1C (rs1006737, P = 0.077). In the psychotic BPD subgroup, as hypothesized, stronger signals were observed in ZNF804A (P = 0.019) and CACNA1C (P = 0.017). We found no association in the ANK3 markers, but the rs10994336 variant was nominally associated with non-psychotic BPD (P = 0.046). Exploratory analysis revealed the rs1344706 variant was also implicated in suicide-attempt behaviour (P = 0.038). Conclusions. These tentative results are consistent with the hypothesis that the subphenotype of BPD with psychosis may represent a clinical manifestation of shared genetic liability between BPD and SCZ.

Association of the α2A adrenergic receptor -1291C/G polymorphism and antipsychotic-induced weight gain in European–Americans

AIMS To investigate the -1291 C/G promoter polymorphism (rs1800544) of the adrenergic alpha-2A receptor (ADRA2A) with clozapine-/olanzapine-induced weight gain in European-Americans and African-Americans. The alpha-adrenergic receptors inhibit lipolysis in the adipose tissue and are involved in weight gain regulation. Moreover, two previous studies indicated an association with antipsychotic-induced weight gain with the same polymorphism in Asian populations. MATERIALS & METHODS We analyzed a relatively large (n=129) and well-characterized group of patients and monitored them for a period of 6-14 weeks. Our refined sample consisted of 60 European-Americans and 39 African-Americans on clozapine or olanzapine, prospectively. RESULTS In European-Americans, we observed a significant difference in weight gain across the genotypic categories (p=0.046). The carriers of the C allele gained more weight compared with the subjects homozygous for the GG allele (CC + CG vs GG; 3.73 +/- 4.13 kg vs 0.23 +/- 2.92 kg; p=0.013). We did not find a significant association in African-Americans, although the sample size was probably too small. CONCLUSION Our observations suggest a possible role of ADRA2A polymorphisms in clozapine-/olanzpaine-induced weight gain in subjects of European descent.