Developmental Dyslexia is a heritable condition, with genetic factors accounting for 44%–75% of the variance in performance tests of reading component subphenotypes. Compelling genetic linkage and association evidence supports a quantitative trait locus in the 6p21.3 region, which encodes a gene called DCDC2. In the present study, we explored the contribution of two DCDC2 markers to dyslexia, related reading and memory phenotypes in nuclear families of Italian origin.
303 nuclear families recruited on the basis of having a proband with Developmental Dyslexia have been studied with 6p21.3 markers, BV677278 and rs793862. Marker-trait association was investigated by the quantitative transmission disequilibrium test (QTDT, version 2.5.1) as modelled by Abecasis et al. (2000), which allows for the analyses of quantitative traits. Seven phenotypes were used in association analyses, i.e. word and non-word reading, word and non-word spelling, orthographic choice, memory and the affected status based on inclusion criteria.
QTDT analyses yielded evidence for association between reading skills and the BV677278 deletion (empirical p-values= .025–.029) and between memory and BV677278 allele 10 (empirical p-value= .0001).
Our result adds further evidence in support of DCDC2 contributing to the deficits in Developmental Dyslexia. More specifically, our data support the view that DCDC2 influences both reading and memory impairments thus shedding further light into the etiologic basis and the phenotypic complexity of Developmental Dyslexia.
DCDC2; Developmental Dyslexia; Transmission Disequilibrium Test; association study
Borderline personality disorder (BPD) is a severe disorder with high morbidity and mortality, but unknown etiology. Childhood abuse has been proposed as an etiological factor, but the mechanism by which an abuse history could influence risk for BPD has not been determined. The aim of this study was to determine whether the Tryptophan Hydroxylase 1 gene is related to BPD in a clinical sample, and whether TPH1 genotypes or haplotypes moderate the relationship between abuse history and BPD.
Three hundred ninety-eight patients diagnosed with mood disorders were genotyped for TPH1 G-6526A promoter polymorphism (rs4537731) and the A218C intron 7 polymorphism (rs1800532) and a set of ancestry informative markers, assessed for DSM IV diagnoses, and assessed for a history of physical and/or sexual abuse.
Patients with a diagnosis of BPD were more likely to be risk allele carriers (A alleles at both loci) than the non-BPD group. Logistic regression analysis predicting BPD diagnosis with both single SNPs and haplotypes showed significant interaction effects between genotype and abuse history. Poisson regression predicting the number of BPD diagnostic criteria met with the same predictor set also included a significant interaction term. Risk allele carriers with a history of abuse had an increased likelihood of a BPD diagnosis.
Variation in TPH1may increase risk for developing BPD as a result of childhood abuse. Elements of BPD pathology may be due in part to a genetically influenced serotonergic dysfunction, which in turn may lead to a differential response to environmental stressors.
TPH1; tryptophan hydroxylase; A218C; G-6526A; Borderline Personality Disorder; Childhood Abuse; Suicide; Impulsivity; Impulsiveness
Depression and alcohol dependence are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35–60%. In addition, evidence from twin studies suggests that alcohol dependence and depression are genetically correlated. Here we report results from a genome-wide association study (GWAS) of a comorbid phenotype in which cases meet the DSM-IV symptom threshold for major depressive symptomatology and DSM-IV criteria for alcohol dependence.
Samples (N=467 cases and N=407 controls) were of European-American descent, and were genotyped using the Illumina Human 1M BeadChip array.
Although no SNP meets genome-wide significance criteria, we identify ten markers with p-values < 1 × 10−5, seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding p<1 × 10−3 are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, alcohol dependence, or other addiction-related phenotypes – such as CDH13, CSMD2, GRID1, and HTR1B – were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an alcohol dependence-only phenotype is modest.
These results underscore the complex genomic influences on psychiatric phenotypes, and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect alcohol dependence alone.
genetics of alcoholism; comorbidity; genetic risk; depressive syndrome
Recent research implicates the COMT Val108/158Met polymorphism in stress-sensitivity, via modulation of hypothalamic-pituitary-adrenal (HPA) function. In healthy samples, Met-homozygosity has been associated with greater HPA activity (i.e., cortisol) and stress sensitivity, though findings are mixed among clinical samples. To date, there are no reports examining baseline or longitudinal changes in HPA activity as a function of COMT genotype in youth. This study examined the association of COMT with salivary cortisol across a one-year period in healthy and at-risk adolescents with DSM-IV-TR Axis II diagnoses. Results indicated higher cortisol levels for Met-homozygotes (compared to heterozygotes and Val homozygotes) at the one-year follow-up, and increased mean cortisol levels across a one-year period among Met-carriers, suggesting that COMT associates with differences in cortisol secretion during adolescence. Findings are discussed with respect to COMT genotype as a potential genetic indicator of psychiatric risk that modulates developmental changes in HPA activity.
genetic; COMT; catechol-o-methyltransferase; psychosis; schizophrenia; stress; risk; cortisol; hypothalamic-pituitary-adrenal axis; HPA
In previous analyses of non-Hispanic white women we found a stronger relation between abuse history and mid-pregnancy elevated depressive symptoms in women with the serotonin transporter (5-HTTLPR) S/S genotype. Here we focus on African-American women (N=698). Our inquiry is motivated by racial differences in depression diagnosis/treatment, stressors and frequency of major 5-HTTLPR alleles (S, LA, LG).
Stressful life events (lifetime) and depressive symptoms (current) were ascertained at 15–27 weeks gestation. A Center for Epidemiological Studies Depression score of ≥18 was considered “elevated”. Life events were scored together and separated into six sub-constructs. 5-HTTLPR genotypes were grouped as follows: 1) L and S alleles, 2) S-LG equivalence (“tri- to biallelic”) and 3) LA/LA, all others, S/S (“high/intermediate/low”). Odds ratios (OR) for “elevated” depressive symptoms-life events (total and sub-constructs) relations were calculated for each genotype grouping.
The prevalence of “elevated” depressive symptoms did not vary by genotype. The relation between stressful life events and “elevated” depressive symptoms was stronger in S/S compared to LA/LA genotype (interaction P=0.11). Of the six sub-constructs, only abuse showed a statistically significant gene-environment interaction. The OR for the abuse- “elevated” depressive symptoms association was greater for S/S vs. LA/LA (interaction P= 0.03) and in the “tri- to biallelic” grouping (interaction P=0.04). In the “high/intermediate/low” grouping, “low” (S/S) had a higher OR (5.5) than both “intermediate” and “high” (ORs≤2.3) (interaction P=0.10).
These results show the importance of examining racial groups, specific stressful events and different 5-HTTLPR genotype groupings when exploring gene-environment interactions in depression.
5-HTTLPR; African American; depressive symptoms; gender; gene-environment interaction; stressful life events; pregnancy; women
Autism is a neurodevelopmental disorder with a strong genetic component to susceptibility. Here, we report the molecular characterization of an apparent de novo 281 kb duplication of Chromosome 2p25.3 in two male half-siblings with autism.
The 2p25.3 duplication was first identified through a low-density microarray, validated with FISH, and duplication breakpoints were delineated using an Affymetrix 6.0 SNP microarray.
FISH results validated the novel copy number variant and revealed the mother to be mosaic, with ~33% of her lymphoblast cells carrying the duplication. Therefore, the duplication was transmitted through the mechanism of germline mosaicism. Additionally, duplication breakpoints were refined and show that PXDN is fully duplicated, while seven exons of the terminal portion of the 25 exon gene MYT1L are within the duplicated region.
MYT1L, a gene predominately expressed in the brain, has recently been linked to other neuropsychiatric illness such as schizophrenia and depression. Results from this study indicate that the 2p25.3 duplication disrupting PXDN and MYT1L is a potential autism-causing variant in the pedigree reported here and should receive further consideration as a candidate gene for autism.
MYT1L; autistic disorder; DNA copy number variations; mosaicism; genetics
Antisocial personality disorder (ASPD) frequently co-occurs with substance dependence (SD). A functional polymorphism (5-HTTLPR) in the serotonin transporter gene has been widely studied as a risk factor for a variety of psychopathologic conditions, including aggressive/violent behavior. Childhood abuse is an important predictor of ASPD. We examined 5-HTTLPR genotype and adverse childhood events (ACEs) as risk factors for ASPD in a SD sample.
Study participants [602 European Americans (EAs) and 779 African Americans (AAs)] were interviewed to obtain lifetime diagnoses of ASPD and SD and information on ACEs. Tri-allelic genotypes for 5-HTTLPR were obtained using standard methods. We used logistic generalized estimating equations (GEE) regression to examine ACEs and 5-HTTLPR genotype and their interaction as predictors of ASPD, separately by population group.
There were 203 (14.7%) participants diagnosed with ASPD. The frequency of the low-activity 5-HTTLPR S’ allele did not differ by ASPD diagnosis, and there was no overall 5-HTTLPR × ACE interaction. However, among EAs, male sex (OR=3.36; p<0.001) and ACE history (OR=1.47; p=0.002) were significant predictors of ASPD. Among AAs, there was a significant interaction of sex × 5-HTTLPR genotype × ACEs (χ2=13.92, p<0.001). Among AA men, each additional ACE significantly increased the odds of ASPD irrespective of genotype, while among AA women, the effect of ACEs on ASPD was significant only among S’ homozygotes. However, these results are limited by the small sample size in each subgroup, (particularly AA women with S’S’ genotype; N=7) and require replication.
Childhood maltreatment contributes to the risk of antisocial personality disorder, an effect for which there is preliminary evidence of moderation by 5-HTTLPR genotype in AA women.
Serotonin Transporter Gene; SLC6A4; Child Abuse; Antisocial Personality Disorder; gene × environment
A recent study in a sample of Plains Indians showed association between eight SNPs located in the SGIP1 gene and resting theta electroencephalogram (EEG) power (Hodgkinson et al., 2010). This association appeared to generalize to alcohol use disorders, for which EEG power is a potential endophenotype.
We analyzed a large, diverse sample for replication of the association of these implicated SGIP1 SNPs (genotyped on the Illumina 1M platform) with alcohol dependence (N = 3988) and theta EEG power (N = 1066).
We found no evidence of association of the previously implicated SGIP1 SNPs with either alcohol dependence or theta EEG power (all p > 0.15) in the current sample.
The previously implicated SNPs located in SGIP1 showed no association with alcohol dependence or theta EEG power in the present sample of individuals with European and/or African ancestry. This failure to replicate may be the result of differences in ancestry between the current and original samples.
alcoholism; electroencephalogram; candidate gene association study
Alcoholism and affective disorders are both strongly comorbid and heritable. We have investigated the genetic comorbidity between bipolar affective disorder and alcoholism.
A genome-wide allelic association study of 506 patients from the University College London (UCL) bipolar disorder case control sample and 510 ancestrally-matched supernormal controls. 143 of the bipolar subjects fulfilled the research diagnostic criteria (RDC) diagnosis of alcoholism. 372,193 single nucleotide polymorphisms (SNPs) were genotyped. Genes previously shown to be associated with alcoholism and addiction phenotypes were then tested for association in the bipolar alcoholic sample using gene wise permutation tests of all SNPs genotyped within a 50kb region flanking each gene.
Several CNS genes showed significant (p<0.05) gene wise evidence of association with bipolar alcoholism. The genes implicated which replicated previously identified associations with alcoholism were: cadherin 11 (CDH11), collagen type XI alpha 2 (COL11A2), neuromedin U receptor 2 (NMUR2), exportin7 (XP07) and semaphorin associated protein 5A (SEMA5A). The SNPs most strongly implicated in bipolar alcoholism, but which did not meet conventional genome-wide significance criteria were the insulin-like growth factor binding protein 7 (IGFBP7), carboxypeptidase O (CPO), cerebellin 2 (CBLN2), and the cadherin 12 (CDH12) genes.
We have confirmed the role of some genes previously shown to be associated with alcoholism in the comorbid bipolar alcoholism subgroup. In this subgroup bipolar disorder may lower the threshold for the phenotypic expression of these alcoholism susceptibility genes. We also show that some genes may independently increase susceptibility to affective disorder and alcoholism.
Bipolar; alcoholism; genome wide association; comorbid; gene wise
Research implicates the A1 allele of the dopamine D2 receptor gene (DRD2) Taq1A polymorphism in the development of depression and anxiety.
Furthermore, recent papers suggest that children with A1 allele of this gene may receive less positive parenting, and that the effects of this gene on child symptoms may be moderated by parenting. We sought to replicate and extend these findings using behavioral measures in a nonclinical sample of young children.
In a sample of 473 preschool-aged children and their mothers, structured clinical interview measures and maternal reports of child symptoms were collected, and standardized observations of parent–child interactions were conducted.
An association was detected between the DRD2 A1 allele and symptoms of depression and anxiety indexed using interview and parent report methods. As found in previous reports, children with the DRD2 A1 allele received less supportive parenting and displayed higher levels of negative emotionality during parent–child interactions. Tests of mediation and moderation were conducted.
We found associations between the DRD2 A1 allele and early-emerging anxious and depressive symptoms in a community sample of preschool-aged children, and evidence of a gene–environment correlation and moderation of the main effect of child genotype on child symptoms by parenting.
anxiety; depression; dopamine D2 receptor gene; parenting
Mood disorders are highly heritable forms of major mental illness. A major breakthrough in elucidating the genetic architecture of mood disorders was anticipated with the advent of genome-wide association studies (GWAS). However, to date few susceptibility loci have been conclusively identified. The genetic etiology of mood disorders appears to be quite complex, and as a result, alternative approaches for analyzing GWAS data are needed. Recently, a polygenic scoring approach that captures the effects of alleles across multiple loci was successfully applied to the analysis of GWAS data in schizophrenia and bipolar disorder (BP). However, this method may be overly simplistic in its approach to the complexity of genetic effects. Data mining methods are available that may be applied to analyze the high dimensional data generated by GWAS of complex psychiatric disorders. We sought to compare the performance of five data mining methods, namely, Bayesian Networks (BN), Support Vector Machine (SVM), Random Forest (RF), Radial Basis Function network (RBF), and Logistic Regression (LR), against the polygenic scoring approach in the analysis of GWAS data on BP. The different classification methods were trained on GWAS datasets from the Bipolar Genome Study (2,191 cases with BP and 1,434 controls) and their ability to accurately classify case/control status was tested on a GWAS dataset from the Wellcome Trust Case Control Consortium. The performance of the classifiers in the test dataset was evaluated by comparing area under the receiver operating characteristic curves (AUC). BN performed the best of all the data mining classifiers, but none of these did significantly better than the polygenic score approach. We further examined a subset of SNPs in genes that are expressed in the brain, under the hypothesis that these might be most relevant to BP susceptibility, but all the classifiers performed worse with this reduced set of SNPs. The discriminative accuracy of all of these methods is unlikely to be of diagnostic or clinical utility at the present time. Further research is needed to develop strategies for selecting sets of SNPs likely to be relevant to disease susceptibility and to determine if other data mining classifiers that utilize other algorithms for inferring relationships among the sets of SNPs may perform better.
data mining; Genome-Wide Association; Mood Disorders
A recent genome-wide association study and follow-up shows significant association with the protocadherin 11 X-linked (PCDH11X) gene. Carrasquillo et al. (2009) show statistical association with four PCDH11X polymorphisms (rs5984894, rs2573905, rs5941047, rs4568761) in five of seven cohorts. The combined analysis of 2,356 cases and 2,384 controls showed the strongest association with a p-value of 2.2 × 10-7 with an allele specific odds ratio of 1.30 (95% CI, 1.18–1.43) at the rs5984894 polymorphism. We tested for association at these four SNPs in two independent datasets and then performed a joint analysis. Though we had adequate power to detect effects sizes with the reported odds ratios, we did not detect association between LOAD and the PCDH11X polymorphisms in our dataset of 889 cases and 850 controls, indicating that the PCDH11X association, if not a false positive, is not as strong or generalized as previously hypothesized.
Alzheimer disease; genetic association study; PCDH11X
This study’s aims were to map loci linked to self-rating of the effects of alcohol and to determine if there was overlap with loci previously mapped for other substance dependence phenotypes in an American Indian community at high risk for substance dependence.
Each participant gave a blood sample and completed a structured diagnostic interview using the Semi Structured Assessment for the Genetics of Alcoholism (SSAGA). Retrospective report of responses to alcohol during the FIRST FIVE TIMES they had ever drank alcohol was estimated from the Self-Rating of the Effects of Alcohol (SRE) questionnaire for each participant. Genotypes were determined for a panel of 791 micro-satellite polymorphisms in 381 members of multiplex families using SOLAR.
Analyses of multipoint variance component LOD scores, for the FIRST FIVE TIMES phenotype, revealed two loci that had a LOD score greater than 3.0 on chromosomes 6 and 9. Additionally, 3 locations were identified with LOD scores above 2.0 on chromosomes 10, 12, 17.
These results corroborate the importance of regions on chromosome 6 and 9 highlighted in prior segregation studies in this and other populations for substance dependence-related phenotypes, as well as an area on chromosome 10 previously identified for the FIRST FIVE TIMES phenotype in the collaborative study on the genetics of alcoholism. These studies additionally lend further support the construct that the SRE may represent an important endophenotype associated with alcohol and other substance dependence.
American Indians; alcohol dependence; linkage studies; SRE
Conduct disorder is a serious, relatively common disorder of childhood and adolescence. Findings from genetic association studies searching for genetic determinants of the liability toward such behaviors have been inconsistent. One possible explanation for differential results is that most studies define phenotype from a single assessment; for many adolescents conduct problems decrease in severity over time, while for others such behaviors persist. Therefore, longitudinal datasets offer the opportunity to refine phenotype.
We utilized Caucasians first assessed during adolescence from the National Youth Survey Family Study. Nine waves of data were utilized to create latent growth trajectories and test for associations between trajectory class and 5HTTLPR genotype.
For the full sample, 5HTTLPR was not associated with conduct problem phenotypes. However, the short (s) allele was associated with chronic conduct problems in females; a nominally significant gender by 5HTTLPR genotype interaction was noted.
Longitudinal studies provide unique opportunities for phenotypic refinement and such techniques, with large samples, may be useful for phenotypic definition with other study designs, such as whole genome association studies.
delinquency; antisocial; genetic association; aggression; serotonin
Owing to the clinical relationship between bipolar disorder and nicotine dependence, we investigated two research questions: (i) are genetic associations with nicotine dependence different in individuals with bipolar disorder as compared with individuals without bipolar disorder, and (ii) do loci earlier associated with nicotine dependence have pleiotropic effects on these two diseases.
Our study consisted of 916 cases with bipolar disorder and 1028 controls. On the basis of known associations with nicotine dependence, we genotyped eight single-nucleotide polymorphisms (SNPs) on chromosome 8 (three bins) in the regions of CHRNB3 and CHRNA6, and six SNPs on chromosome 15 (three bins) in the regions of CHRNA5 and CHRNA3.
To determine whether the genetic associations with nicotine dependence are different in bipolar disorder than in the general population, we compared allele frequencies of candidate SNPs between individuals with nicotine dependence only and individuals with both nicotine dependence and bipolar disorder. There were no statistical differences between these frequencies, indicating that genetic association with nicotine dependence is similar in individuals with bipolar disorder as in the general population. In the investigation of pleiotropic effects of these SNPs on bipolar disorder, two highly correlated synonymous SNPs in CHRNB3, rs4952 and rs4953, were significantly associated with bipolar disorder (odds ratio 1.7, 95% confidence interval: 1.2–2.4, P = 0.001). This association remained significant both after adjusting for a smoking covariate and analyzing the association in nonsmokers only.
Our results suggest that (i) bipolar disorder does not modify the association between nicotine dependence and nicotinic receptor subunit genes, and (ii) variants in CHRNB3/CHRNA6 are independently associated with bipolar disorder. Psychiatr Genet 00:000–000.
analyses; CHRNA3; CHRNA5; CHRNA6; genetic association; nicotine; tobacco use disorder
There have been reports of an association between Darier’s disease, an autosomal dominant genodermatosis, and psychiatric illness. Recently the gene causing Darier’s disease has been mapped to an area on 12q, between D12S58 and D12S84. The findings of linkage analysis of 4 markers in the Darier’s disease region on 12q in five families segregating schizophrenia are presented. They fail to support close linkage between schizophrenia and the Darier’s disease region on 12q.
PMID: 9149323 CAMSID: cams1924
Chromosome 12; Darier’s disease; Linkage; Schizophrenia
A single nucleotide polymorphism (rs7341475) in RELN has recently been shown to be associated with schizophrenia (SZ) in an Ashkenazi Jewish (AJ) case-control study specifically in women by Shifmen et al. We have replicated this association in women in another large independent AJ collection (721 cases, 259 female; 1455 controls, 834 female) and confirmed that it applies to both SZ and schizoaffective disorder. Further, we explore the effects of this polymorphism through quantitative trait loci (QTL) analysis of 9 SZ related factors providing information on sex-specific genotype-phenotype correlations.
Schizophrenia; Reelin; Association; Endophenotype; Sex-specific; Ashkenazi; Jewish
There are theoretical reasons why comparing marker allele frequencies between cases of different diseases, rather than with controls, may offer benefits. The samples may be better matched, especially for background risk factor common to both diseases. Genetic loci may also be detected which influence which of the two diseases occurs if common risk factors are present.
We used samples of UK bipolar and schizophrenic cases which had previously been subject to genome wide association studies and compared marker allele frequencies between the two samples. When these differed for a marker, we compared the case sample allele frequencies with those of a control sample.
Eight markers were significant at p<10−5. Of these, the most interesting finding was for rs17645023 which was significant at p<10−6 and which lies 36kb from CACNG5. Control allele frequencies for this marker were intermediate between those for bipolar and schizophrenic cases.
Application of this approach suggests that it does have some merits. The finding for CACNG5, taken together with the prior implication of CACNA1C and CACNA1B, strongly suggests a key role for voltage-dependent calcium channel genes in the susceptibility to bipolar disorder and/or schizophrenia.
Schizophrenia; bipolar disorder; association; calcium channel
Genome-wide association study was carried out on personality traits among bipolar patients as possible endophenotypes for gene discovery in bipolar disorder.
The subscales of Cloninger’s Temperament and Character Inventory (TCI) and the Zuckerman–Kuhlman Personality Questionnaire (ZKPQ) were used as quantitative phenotypes. The genotyping platform was the Affymetrix 6.0 SNP array. The sample consisted of 944 individuals for TCI and 1007 for ZKPQ, all of European ancestry, diagnosed with bipolar disorder by Diagnostic and Statistical Manual of Mental Disorders-IV criteria.
Genome-wide significant association was found for two subscales of the TCI, rs10479334 with the ‘Social Acceptance versus Social Intolerance’ subscale (Bonferroni P = 0.014) in an intergenic region, and rs9419788 with the ‘Spiritual Acceptance versus Rational Materialism’ subscale (Bonferroni P = 0.036) in PLCE1 gene. Although genome-wide significance was not reached for ZKPQ scales, lowest P values pinpointed to genes, RXRG for Sensation Seeking, GRM7 and ITK for Neuroticism Anxiety, and SPTLC3 gene for Aggression Hostility.
After correction for the 25 subscales in TCI and four scales plus two subscales in ZKPQ, phenotype-wide significance was not reached.
bipolar; genome-wide association study; GRM7; personality; RXRG; Temperament and Character Inventory; Zuckerman–Kuhlman Personality Questionnaire
A family was previously identified that cosegregates a pericentric inversion, inv(3)(p14 : q21), with an early-onset developmental condition, characterized by impulsive behavior and intellectual deficit. The inversion breakpoints lie within DOCK3 and SLC9A9 at the p-arm and q-arm, respectively. Based on this report, these genes were selected to be evaluated in a family-based attention-deficit/hyperactivity disorder (AD/HD) association study.
Conners’ Parent (CPRS) and Teacher (CTRS) Rating Scales of AD/HD symptoms and Conners’ Continuous Performance Test (CPT) measures were collected and a minimal number of tagging singlenucleotide polymorphisms (SNPs) in each gene were selected for analysis. Analyses were performed on families who met research criteria for AD/HD. Using the program, QTDT, each tagging SNP was tested for association with T-scores from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) subscales according to the CTRS and CPRS, and five CPT measures.
After adjusting for multiple testing, a SNP in the 3′ UTR of SLC9A9, rs1046706, remained significantly associated (false discovery rate, q value < 0.05) with scores on the DSM-IV hyperactive-impulsive and total symptom subscales according to the CTRS and errors of commission on the CPT. In addition, an intronic SLC9A9 SNP, rs2360867, remained significantly associated with errors of commission.
Our results suggest that SLC9A9 may be related to hyperactive-impulsive symptoms in AD/HD and the disruption of SLC9A9 may be responsible for the behavioral phenotype observed in the inversion family. The association with SLC9A9 is particularly interesting as it was recently implicated in a genome-wide association study for AD/HD. Further investigation of the role of SLC9A9 in AD/HD and other behavioral disorders is warranted.
attention-deficit/hyperactivity disorder; Conners’ Continuous Performance Test; Conners’ Parent Rating Scale; Conners’ Teacher Rating Scale; genetics; psychiatry; single-nucleotide polymorphism
Variation in the catechol-O-methyltransferase gene (COMT) has been associated with antisocial behavior in ADHD populations. The present study examined whether COMT would predict antisocial behavior in a sample with high levels of behavior problems, not necessarily ADHD. Additionally, because previous research suggests that COMT may be associated with ADHD in males, association between COMT and ADHD symptoms was examined.
The current study tested whether variation in three polymorphisms of the COMT gene was predictive of symptoms of conduct disorder and ADHD, in a sample of 174 incarcerated Russian adolescent male delinquents.
The Val allele of the Val158Met polymorphism was significantly associated with conduct disorder diagnosis and symptoms, whereas the Met allele was associated with ADHD symptoms.
The Val158Met polymorphism of the COMT gene shows a complex relation to behavior problems, influencing conduct disorder and ADHD symptoms in opposite directions in a high-risk population.
Conduct Disorder; ADD/ADHD; antisocial behavior; genetics; catechol-O-methyltransferase