Gender‐specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia

We examined the genetic effect of DRD2 A1 allele in 167 Korean schizophrenics in relation to their smoking habit. Although there was no apparent difference in the genotype distributions of DRD2 gene among the female schizophrenics (n = 66), the male counterpart (n = 101) showed significant differences in their genotype distributions. The comparison between male smoking and non‐smoking patients showed the difference in genotype distribution (P = 0.010) with a higher prevalence of A1 allele (P = 0.020) and frequency of heterozygotes (P = 0.005), but not frequency of the A1 allele. The A1A2 heterozygotes male showed significantly higher smoking rate compared to the A1A1 or A2A2 homozygotes male, and non‐smokers were deficient in heterozygotes. By contrast, among female schizophrenics, the heterozygotes showed a lower smoking rate than homozygotes and there were more heterozygotes in non‐smokers. The deviation from Hardy‐Weinberg expectations was observed in male and female non‐smokers showing quite opposite profiles. Highly significant differences were seen between male and female non‐smokers in A1 prevalence (P = 0.001), genotype distribution (P = 0.00011), and frequency of heterozygotes (P = 0.00003), but not in A1 frequency. The analyses from both male and female as one group showing no significant difference in the genotype distributions between smokers and non‐smokers could be explained by the gender difference in the genetic effect of DRD2 A1 allele. Our findings present the gender‐specific molecular heterosis of DRD2 gene in relation specifically to the smoking status of schizophrenic patients. They indicate the importance of heterosis and gender effects that should be taken into consideration for the association studies. © 2002 Wiley‐Liss, Inc.     

Significant association of DRD2 enhancer variant rs12364283 with heroin addiction in a Pakistani population

The dopamine D2 receptor encoded by DRD2 has been implicated in multiple psychiatric disorders, mediated at least in part by two intronic variants affecting mRNA splicing, rs1076560 and rs2283265, and a less frequent enhancer variant, rs12364283, which increases DRD2 mRNA expression. This study tests whether these functionally validated variants confer susceptibility toward heroin addiction in a Pakistani population. A total of 540 heroin addicts and 467 healthy controls were genotyped, basic allele and genotype tests were performed. Neither rs1076560 nor rs2283265 significantly associated with heroin addiction. The enhancer rs12364283 occurs more frequently in heroin‐dependent cases than controls (MAF 13% vs. 7%, respectively), revealing significant association with heroin addiction (p = 3.0E‐06, OR 2.1). This study identifies rs12364283 of DRD2 as a potential risk factor for heroin addiction in the Pakistani study population. This enhancer variant had been shown to increase DRD2 mRNA expression, a possible factor in increased vulnerability to heroin addiction. Further studies are needed to validate this association of rs12364283.     

The Dopamine Receptor D2 (DRD2) SNP rs1076560 is Associated with Opioid Addiction

The risk for drug addiction is partially heritable. Genes of the dopamine system are likely candidates to harbour risk variants, as dopamine neurotransmission is involved in mediating the rewarding effects of drugs of abuse. One functional single nucleotide polymorphism in dopamine receptor D2 (DRD2), rs1076560, is involved in regulating splicing of the gene and alters the ratio of DRD2 isoforms located pre‐ and postsynaptically. rs1076560 has been previously associated with cocaine abuse and we set out to confirm this association in a sample of European American (EA) (n = 336) and African American (AA) (n = 1034) cocaine addicts and EA (n = 656) and AA (n = 668) controls. We also analysed the role of rs1076560 in opioid dependence by genotyping EA (n = 1041) and AA (n = 284) opioid addicts. rs1076560 was found to be nominally associated with opioid dependence in EAs (p = 0.02, OR = 1.27) and AAs (p = 0.03, OR = 1.43). When both opioid‐addicted ancestral samples were combined, rs1076560 was significantly associated with increased risk for drug dependence (p = 0.0038, OR = 1.29). This association remained significant after correction for multiple testing. No association was found with cocaine dependence. These data demonstrate the importance of dopamine gene variants in the risk for opioid dependence and highlight a functional polymorphism that warrants further study.     

Family‐based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking

A recent study showed an association between the dopamine D2 receptor gene (DRD2) and smoking. The purpose of this study was to determine if the familial transmission of smoking is linked to variation at the DRD2 locus in a genetically informative sample. Subjects were identified in alcohol treatment centers and their relatives were recruited for study. All subjects were interviewed to assess alcohol dependence, smoking habits, and psychiatric disorders. Two polymorphisms within the DRD2 gene were analyzed, including the TaqIA polymorphism. The sample consisted of 138 nuclear families with at least one offspring with habitual smoking, and analysis was by the transmission disequilibrium test (TDT), which avoids problems due to population stratification. There was no significant difference in the frequency between DRD2 alleles transmitted and not transmitted to habitual smokers. There also was no evidence for unequal transmission of DRD2 alleles for the phenotypes “ever smoker” or comorbid alcohol dependence and habitual smoking. This study does not support linkage of the DRD2 with smoking. Am. J. Med. Genet. 90:299–302, 2000. © 2000 Wiley‐Liss, Inc.     

Converging evidence implicates the dopamine D3 receptor gene in vulnerability to schizophrenia

The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine‐to‐serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3), rs6280, has been widely studied for its association with SZ, but with conflicting results. Altered levels of DRD3 mRNA have also been reported in SZ compared with normal controls. Moreover, it has been suggested that DRD3 is subject to recent positive selection in European populations. To explore the potential role of DRD3 in SZ from these various aspects, we conducted a threefold study. First, we tested the genetic association of rs6280 with SZ in 685 SZ patients and 768 normal controls. Second, we examined DRD3 mRNA levels in peripheral leukocytes in a subset of 37 patients and 37 controls. Finally, we investigated the possible recent positive selection on DRD3 in an East Asian population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P = 0.045), with the ancestral CC genotype being significantly over‐represented in SZ patients. DRD3 mRNA levels were significantly lower in patients than in controls (P = 5.91E?5). The derived C‐allele of rs6280 might have been subject to recent positive selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural selection, might be involved in vulnerability to SZ in the Han Chinese population. These findings may further add to the body of data implicating DRD3 as a schizophrenia risk gene. © 2011 Wiley‐Liss, Inc.     

Overlapping Dopaminergic Pathway Genetic Susceptibility to Heroin and Cocaine Addictions in African Americans

Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine‐related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). Single‐marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7‐SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent.     

Genetics and Mental Retardation Syndromes,by Elisabeth M. Dykens,Robert M. Hodapp,and Brenda M. Finucane

Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case‐control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( ± five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over‐representation of genotype 5‐5 (P = 0.004) and allele 5 (P = 0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations. © 2002 Wiley‐Liss, Inc.     

An association study of DRD2 gene polymorphisms with schizophrenia in a Chinese Han population

Dopamine signaling is strongly implicated in the etiology of schizophrenia (SZ). Because of the essential role dopamine D2 receptor (DRD2) in dopamine signaling, DRD2 gene has been regarded as one of the top candidate genes for SZ. However, the findings from linkage and association analyses on this gene are mixed and largely inconsistent across various studies. The aim of this study is to investigate the correlation of DRD2 gene variation and the risk for SZ in a Chinese Han population. Three SNPs (rs1801028, rs6275 and rs6277) of DRD2 gene were genotyped in a patient–control sample involving 421 SZ patients and 404 healthy controls. Our data indicated a nominally significant association of rs6277 with SZ, with T-allele being the risk allele (OR = 1.58, 95%CI = 1.03–2.43, P = 0.034). This study suggests that rs6277 T-allele may play a role in the genetic vulnerability for SZ, supporting the involvement of DRD2 gene in SZ pathogenesis.     

Association between polymorphisms of DRD2 and DRD4 and opioid dependence: Evidence from the current studies

Several studies have assessed the association between genetic polymorphisms of DRD2 and DRD4 genes and opioid dependence risk, while the results were inconsistent. We performed a meta‐analysis, including 6,846 opioid dependence cases and 4,187 controls from 22 individual studies, to evaluate the roles of four variants (DRD2 ?141ins/delC, rs1799732; DRD2 311 Ser > Cys, rs1801028; DRD2‐related TaqI A, rs1800497 and DRD4 exon III VNTR) in opioid dependence for the first time. We found that the ?141delC polymorphism was significantly associated with increased risk of opioid dependence (homozygote comparison: odds ratios [OR], 2.71; 95% confidence interval [CI], 1.74–4.22; dominant comparison: OR, 1.27; 95% CI, 1.09–1.48). Similarly, the TaqI A1 polymorphism was also significantly increased opioid dependence risk (homozygote comparison: OR, 2.06; 95% CI, 1.25–3.42; dominant comparison: OR, 1.34; 95% CI, 1.08–1.67). Moreover, long allele (≥5‐repeat) and 7‐repeat allele of DRD4 exon III VNTR were found to be associated with significantly increased opioid dependence risk (OR, 1.50; 95% CI, 1.24–1.80 and OR, 1.57; 95%, 1.18–2.09, respectively). However, no association was detected between the DRD2 311 Ser > Cys polymorphism and opioid dependence. In conclusion, our results suggested that DRD2 ?141ins/delC, DRD2‐related TaqI A and DRD4 exon III VNTR polymorphisms might play important roles in the development of opioid dependence. © 2011 Wiley‐Liss, Inc.     

Attention‐deficit hyperactivity disorder: A study of association with both the dopamine transporter gene and the dopamine D4 receptor gene

Attention‐deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Several investigations have reported associations between ADHD and both the 7‐repeat allele of the 48 bp VNTR at the DRD4 gene and the 10‐repeat allele of the 40 bp VNTR at the DAT1 gene, but the results have been inconsistent. A sample of 81 Brazilian ADHD children and adolescents and their parents were screened for these DRD4 and DAT1 VNTRs. An excess of the DRD4 7‐repeat allele was observed when both ADHD probands and their parents were compared with an ethnically matched control sample (chi‐square = 11.55, P = 0.03; chi‐square = 12.17, P = 0.03, respectively). However, haplotype relative risk (HRR) analysis showed no preferential transmission of the DRD4 7‐repeat allele. No evidence of association with the DAT1 polymorphism was detected by both approaches. Nevertheless, an interaction effect of both genes on ADHD hyperactive/impulsive dimension was observed (F = 4.68; P = 0.03). These results add to the group of studies that together suggest a small effect of these genes in the susceptibility to ADHD. © 2001 Wiley‐Liss, Inc.     

Association of functional variants in the dopamine D2-like receptors with risk for gambling behaviour in healthy Caucasian subjects

Pathological gambling (PG) is an impulse control disorder with suggestive genetic vulnerability component. We evaluated the association of genetic variants in the dopaminergic receptor genes (DRD1-3s) with risk for gambling in healthy subjects using the Canadian Problem Gambling Index (CPGI). Healthy Caucasian subjects who had gambled at least once in their lifetime (n = 242) were included in the analysis. Gender was not associated with the CPGI, while younger age was associated with higher CPGI scores. We have found that none of the single polymorphisms investigated on DRD1 and DRD3 were associated with CPGI scores in healthy subjects. However, we observed trends for association on the TaqIA/rs1800497 polymorphism (P = 0.10) and the haplotype flanking DRD2 (G/C/A rs11604671/rs4938015/rs2303380; P = 0.06). Both trends were associated with lower CPGI score. Our results provide further evidence for the role of dopamine D2-like receptor in addiction susceptibility.     

An Assessment of Transmission Disequilibrium Between Quantitative Measures of Childhood Problem Behaviors and DRD2/Taql and DRD4/48bp-Repeat Polymorphisms

In a pilot study of 120 children with reading disabilities, we assessed the presence of linkage and association between the DRD2/Taql and the DRD4/48bp-repeat polymorphisms and quantitative measures of behavioral problems derived from parental rated Child Behavior Checklist (CBCL) [Achenbach, T. M. (1991). TM Manual for the CBCL 14-18. Burlington, VT: University of Vermont]. Analyses included measures of between-family association, and a test of the presence of linkage and association by a logistic regression-based extension of the Transmission Disequilibrium Test (i.e., the logistic regression quantitative TDT). In between-family association analyses the "Social Problem" scale was weakly associated with the number of risk alleles of DRD2 and DRD4, while the "Withdrawn" scale was related to the number of risk alleles of DRD4 (the 7-repeat and the A1 allele respectively were considered the risk alleles). Logistic regression quantitative TDTs yielded statistically significant evidence in favor of linkage and association between DRD2 and "Social Problems" (Wald chi2 = 4.13, df = 1, p = 0.042, odds ratio = 1.97). A statistical trend in favor of linkage and association was found for "Withdrawn" and DRD4 (Wald chi2 = 2.65, df = 1, p = 0.104, odds ratio =1.44). Although preliminary, these findings are consistent with previous data that suggest a role of the same polymorphism in influencing individual sensitivity to reward and response to social cues and reinforcements in man and animal.     

Effect of model choice in genetic association studies: DRD4 exon III VNTR and cigarette use in young adults

A major concern with the vast literature associating the highly polymorphic 48 bp VNTR in exon III of the human dopamine receptor D4 gene (DRD4) with various behavioral phenotypes is the lack of concordance between studies. Part of the problem arises from the absence of a universally accepted scheme for pooling the large number of low frequency genotypes into appropriate categories. Here, we investigated the effect of different pooling strategies and genetic models on the reported association between DRD4‐exIII‐VNTR polymorphism and cigarette smoking. Genotyping was performed on a large randomly selected community‐based sample of 2,274 individuals aged 20–24 years. Participants were grouped into sub‐samples based on their genotypes to test specific genetic models. Multiple regression analyses were used to assess the relationship between DRD4‐exIII‐VNTR genotype and cigarette smoking measures while controlling for confounders. While smoking status and age at start of smoking were not associated with the genotype, a significantly (P = 0.006) higher rate of cigarette consumption was observed among carriers of the 7‐repeat (7r) allele. Thus, 7r carriers were not more likely to be smokers but if they did smoke they consumed significantly more cigarettes per day than 4r carriers. Unlike previous studies this association was observed only when comparing carriers of the 7r with the 4r but not the other repeat alleles. Our study demonstrates the need for caution when grouping functionally different DRD4‐exIII‐VNTR alleles in association studies. It particularly highlights the requirement for better functional characterization of the DRD4‐exIII‐VNTR alleles for interpreting results from association studies. © 2011 Wiley‐Liss, Inc.     

Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: A meta‐analysis in four European populations

Attention‐deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4–8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition or in partial remission with persistence of symptoms. Pharmacological, animal and molecular genetic studies support a role for genes of the dopaminergic system in ADHD due to its essential role in motor control, cognition, emotion, and reward. Based on these data, we analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single‐marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiple‐marker meta‐analysis showed a nominal association (P = 0.02) of the L‐4R haplotype (dup120bp‐48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since we previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R‐6R haplotype (3′UTR VNTR‐intron 8 VNTR) in the same dataset, we further tested for gene × gene interaction between DRD4 and SLC6A3. However, we detected no epistatic effects but our results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene. © 2011 Wiley‐Liss, Inc.     

Association analysis in an evolutionary context: Cladistic analysis of the DRD2 locus to test for association with alcoholism

Previous studies testing the dopamine D2 receptor (DRD2) locus for association with alcoholism have produced conflicting results. Failure to screen controls for substance abuse and failure to assess alcoholics for severity have been proposed as causes for the inability of some studies to detect an association. We have reevaluated the involvement of DRD2 mutations in susceptibility to alcoholism with a cladistics-based association analysis after restricting an alcoholic sample to more severe cases. For the present study we tested 55 alcoholic probands and 80 normal controls for differences in the frequency of six haplotypes at the DRD2 locus. The haplotypes were derived from five di-allelic polymorphisms spanning all but the first exon of the DRD2 gene. A cladogram constructed from the haplotypes provided the evolutionary context for a nested statistical analysis. We found no significant evidence for association of the DRD2 haplotypes analyzed with the more severe alcoholic phenotype. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:411–419, 1998. © 1998 Wiley-Liss, Inc.     

An association study of DRD5 with smoking initiation and progression to nicotine dependence

A large body of genetic epidemiological data strongly implicate genetic factors in the etiology of smoking behavior. Polymorphisms of genes in the dopaminergic system are plausible functional candidate genes and a linkage and an association study suggested that the type 5 dopamine receptor gene (DRD5) may be etiologically involved. We investigated the association of four DRD5 polymorphisms with smoking initiation and progression to nicotine dependence in a population-based sample of over 900 subjects. For smoking initiation, there was no significant association with the four DRD5 markers we studied; however, maximum likelihood analyses suggested the presence of a haplotype protective against smoking initiation. For progression to nicotine dependence, there were no strongly significant associations with the four DRD5 markers or for the estimated haplotypes. These data are not consistent with a strong etiological role for DRD5 in the etiology of these complex smoking behaviors.     

An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults

Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self‐reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3′UTR and intron 8 of DAT1, the 10‐repeat and 6‐repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7‐repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS‐G and CAARS‐H (DSM‐IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS‐G was also found for the 7‐repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults. © 2015 Wiley Periodicals, Inc.     

A common variant association study reveals novel susceptibility loci for low HDL‐cholesterol levels in ethnic Arabs

The genetic susceptibility to acquiring low high density lipoprotein‐cholesterol (LHDLC) levels is not completely elucidated yet. In this study, we performed a common variant association study for harboring this trait in ethnic Arabs. We employed the Affymetrix high‐density Axiom Genome‐Wide ASI Array (Asian population) providing a coverage of 598,000 single nucleotide variations (SNPs) to genotype 5495 individuals in a two‐phase study involving discovery and validation sets of experiments. The rs1800775 [1.31 (1.22–1.42); p = 3.41E‐12] in the CETP gene and rs359027 [1.26 (1.16–1.36); p = 2.55E‐08] in the LMCD1 gene were significantly associated with LHDLC levels. Furthermore, rs3104435 [1.26 (1.15–1.38); p = 1.19E‐06] at the MATN1 locus, rs9835344 [1.16 (1.08–1.26); p = 8.75E‐06] in the CNTN6 gene, rs1559997 [1.3 (1.14–1.47); p = 9.48E‐06] in the SDS gene and rs1670273 [1.2 (1.1–1.31); p = 4.81E‐06] in the DMN/SYNM gene exhibited suggestive association with the disorder. Seven other variants including rs1147169 in the PLCL1 gene, rs10248618 in the DNAH11, rs476155 in the GLIS3, rs7024300 in the ABCA1, intergenic rs10836699, rs11603691 in P2RX3 and rs750134 in CORO1C gene exhibited borderline protective properties. Validation and joint meta‐analysis resulted in rs1800775, rs3104435 and rs359027 retaining their predisposing properties, while rs10836699 and rs11603691 showed protective properties. Our data show several predisposing variants across the genome for LHDLC levels in ethnic Arabs.     

DJ‐1 is a Parkinson's disease susceptibility gene in southern Italy

De Marco EV, Annesi G, Tarantino P, Nicoletti G, Civitelli D, Messina D, Annesi F, Arabia G, Salsone M, Condino F, Novellino F, Provenzano G, Rocca FE, Colica C, Morelli M, Scornaienchi V, Greco V, Giofrè L, Quattrone A. DJ‐1 is a Parkinson's disease susceptibility gene in southern Italy. Mutations in the gene DJ‐1 have been shown to be a rare cause of early‐onset Parkinson's disease (EOPD). Since DJ‐1 mutations have been found in patients with Parkinson's disease (PD) from southern Italy, we aimed to investigate whether polymorphisms within the DJ‐1 gene could represent a risk factor for sporadic PD. First, we genotyped 294 patients with PD and 298 controls coming from southern Italy to assess the distribution of the insertion/deletion (Ins/Del) polymorphism. In a second phase, we identified five single‐nucleotide polymorphisms (SNPs) useful to delimit a region potentially involved and genotyped all patients and controls for these markers. All the markers analyzed were significantly associated with PD at both allelic and genotypic level. The most significant association with the disease was found at the Ins/Del polymorphism (p = 0.0001; adjusted odds ratio (OR ) = 2.05; confidence interval (CI ) = 1.36–3.08). When we considered a three‐marker sliding window, we found a highly significant association between the disease and the haplotypes including markers rs17523802, Ins/Del, and rs3766606 (p = 0.0007) and markers Ins/Del, rs3766606 and rs7517357 (p = 0.0054). Our results indicate that polymorphisms located in a region spanning 3535 bp from the promoter to the intron 2 of the DJ‐1 gene confer risk to sporadic PD in southern Italy.     

No association of genetic variants in BDNF with major depression: A meta‐ and gene‐based analysis

Major depressive disorder (MDD) is a complex psychiatric condition with strong genetic predisposition. The association of MDD with genetic polymorphisms, such as Val66Met (rs6265), in the brain derived neurotrophic factor (BDNF), have been reported in many studies and the results were conflicting. In this study, we performed a systematic literature search and conducted random‐effects meta‐analysis to evaluate genetic variants in BDNF with MDD. A gene‐based analysis was also conducted to investigate the cumulative effects of genetic polymorphisms in BDNF. A total of 28 studies from 26 published articles were included in our analysis. Meta‐analysis yielded an estimated odds ratio (OR) of 0.96 (95% CI: 0.89–1.05; P = 0.402) for Val66Met (rs6265), 0.83 (95% CI: 0.67–1.04; P = 0.103) for 11757C/G, 1.16 (95% CI: 0.74–1.82; P = 0.527) for 270T/C, 1.03 (95% CI: 0.18–5.75; P = 0.974) for 712A/G and 0.98 (95% CI: 0.85–1.14; P = 0.831) for rs988748. The gene‐based analysis indicated that BDNF is not associated with MDD (P > 0.21). Our updated meta‐ and novel gene‐based analyses provide no evidence of the association of BDNF with major depression. © 2012 Wiley Periodicals, Inc.