Showing papers in "American Journal of Medical Genetics in 2008"

Genome-wide association scan of quantitative traits for Attention Deficit Hyperactivity Disorder identifies novel associations and confirms candidate gene associations

Abstract: Attention deficit hyperactivity disorder (ADHD) is a complex condition with environmental and genetic etiologies. Up to this point, research has identified genetic associations with candidate genes from known biological pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. We generated six quantitative phenotypes from 18 ADHD symptoms to be used in genome-wide association analyses. With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 and rs552655 that met the criteria for significance within a specified phenotype. These SNPs are located in intronic regions of genes CDH13 and GFOD1, respectively. CDH13 has been implicated previously in substance use disorders. We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori. These findings, along with association P-values with a magnitude less than 10(-5), are discussed in this manuscript. Seventeen of these candidate genes had association P-values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, and COMT. Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test P-values lower than 0.01 and multiple association P-values at a magnitude of 10(-5) in this gene. In sum, these findings identify novel genetic associations at viable ADHD candidate genes and provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed genetic variants for ADHD.

Defining Key Features of the Broad Autism Phenotype : A Comparison Across Parents of Multiple-and Single-Incidence Autism Families

Abstract: This study examined the frequency of personality, language, and social-behavioral characteristics believed to comprise the broad autism phenotype (BAP), across families differing in genetic liability to autism. We hypothesized that within this unique sample comprised of multiple-incidence autism families (MIAF), single-incidence autism families (SIAF), and control Down syndrome families (DWNS), a graded expression would be observed for the principal characteristics conferring genetic susceptibility to autism, in which such features would express most profoundly among parents from MIAFs, less strongly among SIAFs, and least of all among comparison parents from DWNS families, who should display population base rates. Analyses detected linear expression of traits in line with hypotheses, and further suggested differential intrafamilial expression across family types. In the vast majority of MIAFs both parents displayed BAP characteristics, whereas within SIAFs, it was equally likely that one, both, or neither parent show BAP features. The significance of these findings is discussed in relation to etiologic mechanisms in autism and relevance to molecular genetic studies.

The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies

Abstract: Serotonin Transporter (5HTTor SLC6A4) mRNA transcription is regulated by both genetic and epigenetic mechanisms. Unfortunately, despite intense scrutiny, the exact identity and contribution of each of these regulatory mechanisms, and their relationship to behavioral illness remain unknown. This lack of knowledge is critical because alterations in SLC6A4 function are posited to be central to a wide variety of CNS disorders. In order to address this shortcoming, we quantified 5HTTLPR genotype, SLC6A4 mRNA production and CpG methylation using biomaterial from 192 lymphoblast cell lines derived from subjects who participated in the latest wave of the Iowa Adoption Studies. We then analyzed the resulting data with respect to clinical characteristics. We confirmed prior findings that the short (s) 5HTTLPR allele is associated with lower amounts of mRNA transcription, but there was no significant effect of the “Long G” allele on mRNA transcription. We also found that CpG methylation was higher (P< 0.0008) and mRNA production (P< 0.0001) was lower in females as compared to males. Those subjects with a lifetime history of Alcohol Dependence had higher levels of SLC6A4 mRNA. There was a trend for an association of increased overall methylation with lifetime history of major depression. Finally, we confirm our prior findings that the exact levels of 5HTT mRNA expression are dependent on how it is measured. We conclude that both genetic variation and epigenetic modifications contribute to the regulation of SLC6A4 function and that more in-depth studies of the molecular mechanisms controlling gene activity and the relationship of these mechanisms to behavioral illness are indicated.

Genome-wide association scan of attention deficit hyperactivity disorder

Abstract: Results of behavioral genetic and molecular genetic studies have converged to suggest that genes substantially contribute to the development of attention deficit/hyperactivity disorder (ADHD), a common disorder with an onset in childhood. Yet, despite numerous linkage and candidate gene studies, strongly consistent and replicable association has eluded detection. To search for ADHD susceptibility genes, we genotyped approximately 600,000 SNPs in 958 ADHD affected family trios. After cleaning the data, we analyzed 438,784 SNPs in 2,803 individuals comprising 909 complete trios using ADHD diagnosis as phenotype. We present the initial TDT findings as well as considerations for cleaning family-based TDT data. None of the SNP association tests achieved genome-wide significance, indicating that larger samples may be required to identify risk loci for ADHD. We additionally identify a systemic bias in family-based association, and suggest that variable missing genotype rates may be the source of this bias.

Analysis of DRD4 and DAT polymorphisms and behavioral inhibition in healthy adults: implications for impulsivity.

Abstract: Impulsivity, a highly prevalent symptom in multiple psychiatric disorders, is a partially heritable trait influenced by specific biological mechanisms. In particular, dopamine is proposed to play a role in impulsive behaviors and recent studies have implicated functional polymorphisms of dopamine-related genes in impulsive behaviors across different clinical and behavioral classifications. However, most have not isolated the impulsivity construct per se as a biologically based and measurable endophenotype. The present study was therefore undertaken in a sample of healthy adults to investigate the influence of two candidate dopaminergic gene polymorphisms (DRD4 and DAT) on the endophenotype of impulsivity, which we operationalized as behavioral inhibition during the Stop-signal task. We recruited an ethnically diverse sample of 119 healthy adults to complete a self-report questionnaire of impulsivity and to perform a Stop-signal task. We report significant differences in inhibitory control between individuals with at least one 7-repeat allele of the DRD4 polymorphism, as well as an interaction between DRD4 and DAT genotypes, on inhibitory control. Results of the present study support the influence of dopaminergic variation on impulsive-related measures, as well as the advantage of using measures which are likely more sensitive to the effects of such genetic variation.

Clock genes may influence bipolar disorder susceptibility and dysfunctional circadian rhythm.

Abstract: Several previous studies suggest that dysfunction of circadian rhythms may increase susceptibility to bipolar disorder (BP). We conducted an association study of five circadian genes (CRY2, PER1-3, and TIMELESS) in a family collection of 36 trios and 79 quads (Sample I), and 10 circadian genes (ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CSNK1D, CSNK1E, DBP, and NR1D1) in an extended family collection of 70 trios and 237 quads (Sample II), which includes the same 114 families but not necessarily the same individuals as Sample I. In Sample II, the Sibling-Transmission Disequilibrium Test (sib-tdt) analysis showed nominally significant association of BP with three SNPs within or near the CLOCK gene (rs534654, P = 0.0097; rs6850524, P = 0.012; rs4340844, P = 0.015). In addition, SNPs in the ARNTL2, CLOCK, DBP, and TIMELESS genes and haplotypes in the ARNTL, CLOCK, CSNK1E, and TIMELESS genes showed suggestive evidence of association with several circadian phenotypes identified in BP patients. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. A multi-locus interaction between rs6442925 in the 5' upstream of BHLHB2, rs1534891 in CSNK1E, and rs534654 near the 3' end of the CLOCK gene, however, is significantly associated with BP (P = 0.00000172). It remains significant after correcting for multiple testing using the False Discovery Rate method. Our results indicate an interaction between three circadian genes in susceptibility to bipolar disorder.

Meta-Analysis of Genome-Wide Linkage Scans of Attention Deficit Hyperactivity Disorder

Abstract: Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P(SR) = 0.00034, P(OR) = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes.

DSM-IV combined type ADHD shows familial association with sibling trait scores: a sampling strategy for QTL linkage.

Abstract: Attention deficit hyperactivity disorder (ADHD) is a discrete clinical syndrome characterized by the triad of inattention, hyperactivity, and impulsivity in the context of marked impairments. Molecular genetic studies have been successful in identifying genetic variants associated with ADHD, particularly with DSM-IV inattentive and combined subtypes. Quantitative trait locus (QTL) approaches to linkage and association mapping have yet to be widely used in ADHD research, although twin studies investigating individual differences suggest that genetic liability for ADHD is continuously distributed throughout the population, underscoring the applicability of quantitative dimensional approaches. To investigate the appropriateness of QTL approaches, we tested the familial association between 894 probands with a research diagnosis of DSM-IV ADHD combined type and continuous trait measures among 1,135 of their siblings unselected for phenotype. The sibling recurrence rate for ADHD combined subtype was 12.7%, yielding a sibling recurrence risk ratio (lambda(sib)) of 9.0. Estimated sibling correlations around 0.2-0.3 are similar to those estimated from the analysis of fraternal twins in population twin samples. We further show that there are no threshold effects on the sibling risk for ADHD among the ADHD probands; and that both affected and unaffected siblings contributed to the association with ADHD trait scores. In conclusion, these data confirm the main requirement for QTL mapping of ADHD by demonstrating that narrowly defined DSM-IV combined type probands show familial association with dimensional ADHD symptom scores amongst their siblings.

MAOA Methylation is Associated with Nicotine and Alcohol Dependence in Women

Abstract: In recent years, the role of epigenetic phenomenon, such as methylation, in mediating vulnerability to behavioral illness has become increasingly appreciated. One prominent locus at which epigenetic phenomena are thought to be in play is the monoamine oxidase A (MAOA) locus. In order to examine the role of methylation at this locus, we performed quantitative methylation analysis across the promoter region of this gene in lymphoblast lines derived from 191 subjects participating in the Iowa Adoption Studies (IAS). We analyzed the resulting data with respect to genotype and lifetime symptom counts for the more common major behavioral disorders in the IAS, antisocial personality disorder (ASPD), and substance use disorders (alcohol (AD) and nicotine dependence (ND)). We found that methylation status was significantly associated with lifetime symptom counts for ND (P < 0.001) and AD (P < 0.008) in women, but not men. Furthermore, a trend was found for women homozygous for the 3,3 allele to have a higher degree of overall methylation than women homozygous for the 4,4 allele (P < 0.10). We conclude that methylation of MAOA may play a significant role in common psychiatric illness and that further examination of epigenetic processes at this locus is in order.

Cognitive dysfunction in mice deficient for TNF- and its receptors.

Abstract: Recent evidence suggests a role for tumor necrosis factor alpha (TNF) in the functioning of the central nervous system (CNS). The aim of this work was to examine the effect of a deficiency of TNF (TNF(-/-)) and its main receptors (TNF-R1(-/-) and TNF-R2(-/-)) on cognitive function. A standardized survey on cognition-like behavior assessing learning and retention, spatial learning/memory, cognitive flexibility, and learning effectiveness was used in B6.WT and B6.TNF gene targeted mice strains (B6.wild-type, B6.TNF(-/-), B6.TNF-R1(-/-), B6.TNF-R2(-/-) mice). All studied mice strains demonstrated successful exploration and learning processes during the training phases of the tests, which made the specific cognition-like tests valid in these mice strains. In the specific cognition-like tests, the B6.TNF(-/-) mice demonstrated significantly poorer learning and retention in the novel object test compared to B6.WT, B6.TNF-R1(-/-) and B6.TNF-R2(-/-) mice. In addition, spatial learning and learning effectiveness were significantly poorer in B6.TNF(-/-) mice compared to B6.WT mice. Moreover, the moderately impaired cognitive performance with similar degrees in B6.TNF-R1(-/-) or B6.TNF-R2(-/-) mice was generally better than in TNF(-/-) mice but also poorer than in B6.WT mice. While the absence of TNF was correlated with poor cognitive functioning, the deletion of both TNF-receptors was involved in partially reduced cognitive functioning. Low-levels of TNF under non-inflammatory immune conditions appear essential for normal cognitive function. TNF displays an interesting candidate gene for cognitive function. Translational research is required to investigate associations between genetic variants of TNF and cognitive function in healthy subjects and neuropsychiatric samples.

The BDNF Val66Met × 5-HTTLPR × child adversity interaction and depressive symptoms: An attempt at replication

Abstract: Kaufman et al. [2006] reported a higher order interaction effect between specific genetic and environmental factors in a model of depressive symptoms, requiring independent replication. BDNF Val66Met and 5-HTTLPR genotypes were determined in female participants pertaining to a large ongoing twin study. Participants also filled in questionnaires on childhood adversity and depressive symptoms. Two- and three-way interactions between genetic polymorphisms and early adversity were examined in models of depressive symptoms. BDNF Met allele(s) moderated the effect of early adversity on depressive symptoms (two-way interaction), and this BDNF Met × childhood adversity interaction in turn was moderated by 5-HTTLPR genotype (three-way interaction). However, a main effect of BDNF Met on childhood adversity was also observed, possibly indicating confounding by gene–environment correlation. Higher order interaction effects involving BDNF Val66Met, 5-HTTLPR and childhood adversity may contribute to the etiology of depressive illness. © 2007 Wiley-Liss, Inc.

Conduct disorder and ADHD: evaluation of conduct problems as a categorical and quantitative trait in the international multicentre ADHD genetics study.

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by inattention, excessive motor activity, impulsivity, and distractibility. Individuals with ADHD have significant impairment in family and peer relations, academic functioning, and show high co-morbidity with a wide range of psychiatric disorders including oppositional defiant disorder (ODD), conduct disorder (CD), anxiety disorder, depression, substance abuse, and pervasive developmental disorder (PDD). Family studies suggest that ADHD + CD represents a specific subtype of the ADHD disorder with familial risk factors only partly overlapping with those of ADHD alone. We performed a hypothesis-free analysis of the GAIN–ADHD sample to identify markers and genes important in the development of conduct problems in a European cohort of individuals with ADHD. Using the Family-Based Association Test (FBAT) package we examined three measures of conduct problems in 1,043,963 autosomal markers. This study is part of a series of exploratory analyses to identify candidate genes that may be important in ADHD and ADHD-related traits, such as conduct problems. We did not find genome-wide statistical significance (P < 5 × 10−7) for any of the tested markers and the three conduct problem traits. Fifty-four markers reached strong GWA signals (P < 10−5). We discuss these findings in the context of putative candidate genes and the implications of these findings in the understanding of the etiology of ADHD + CD. We aimed to achieve insight into the genetic etiology of a trait using a hypothesis-free study design and were able to identify a number of biologically interesting markers and genes for follow-up studies.

Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis.

Abstract: The serotonin transporter gene (5-HTT) plays a crucial role in serotonergic neurotransmission and has been found to be associated, with varying degrees of significance, with many diseases, including autism. Prior association studies of autism have yielded conflicting results regarding the association between two common 5-HTT polymorphisms, the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR). We conducted a systematic review and meta-analysis to test the following hypotheses: (i) there is an association between autism and either or both of the 5-HTTLPR and STin2 VNTR polymorphisms, and (ii) the S allele of 5-HTTLPR and/or the STin2.12 allele of the VNTR are the specific risk alleles for autism. All published family-based and population based studies were examined to determine the overall strength of association between 5-HTT polymorphisms and autism. After exclusion of studies with overlapping samples and studies whose data did not allow for calculation of an odds ratio, 16 studies were included for final analyses, all but two of which used a family-based design. The meta-analysis failed to find a significant overall association between either of the 5-HTT polymorphisms examined and autism. Further, no allelic transmission distortion was found when studies of simplex (11 studies) and multiplex (3 studies) family samples were analyzed separately. However, there was significant heterogeneity by ethnicity; family based studies of US mixed population samples showed preferential transmission of the S allele of 5-HTTLPR (S allele:L allele = 247:183), while there was no allelic distortion among the family-based studies of European and Asian samples.

Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene.

Abstract: Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P < 0.05) in either a genotypic or allelic association test. All of these genes, except transcription factor DLX1, are involved in the adhesion between neurons and radial glial cells. Eight markers obtained nominal significance in both tests, and were located in intronic or 3′UTR regions of adhesion molecule MDGA1 and previously reported SZ candidate RELN. The most significant result was attained for MDGA1 SNP rs9462341 (unadjusted association results: genotypic P = 0.00095; allelic P = 0.010). Several haplotypes within MDGA1, RELN, ITGA3, and ENAH were nominally significant. Further studies in independent samples are needed, including upcoming genome wide association study results, but our data suggest that MDGA1 is a new SZ susceptibility gene, and that altered neuronal migration is involved in SZ pathology. © 2008 Wiley-Liss, Inc.

Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder.

Abstract: A time-to-onset analysis for family-based samples was performed on the genomewide association (GWAS) data for attention deficit hyperactivity disorder (ADHD) to determine if associations exist with the age at onset of ADHD. The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array. After data cleaning procedures, 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest. No SNP achieved genome-wide significance, and the lowest P-values had a magnitude of 10(-7). Several SNPs among a pre-specified list of candidate genes had nominal associations including SLC9A9, DRD1, ADRB2, SLC6A3, NFIL3, ADRB1, SYT1, HTR2A, ARRB2, and CHRNA4. Of these findings SLC9A9 stood out as a promising candidate, with nominally significant SNPs in six distinct regions of the gene.

Autism spectrum conditons in myotonic dystrophy type 1: A study on 57 individuals with congenital and childhood forms

Abstract: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder, caused by an expansion of a CTG triplet repeat in the DMPK gene. The aims of the present study were to classify a cohort of children with DM1, to describe their neuropsychiatric problems and cognitive level, to estimate the size of the CTG expansion, and to correlate the molecular findings with the neuropsychiatric problems. Fifty-seven children and adolescents (26 females; 31 males) with DM1 (CTG repeats > 40) were included in the study. The following instruments were used: Autism Diagnostic Interview-Revised (ADI-R), 5-15, Griffiths Mental Development Scales, and the Wechsler Scales. Based on age at onset and presenting symptoms, the children were divided into four DM1 groups; severe congenital (n = 19), mild congenital (n = 18), childhood (n = 18), and classical DM1 (n = 2). Forty-nine percent had an autism spectrum disorder (ASD) and autistic disorder was the most common diagnosis present in 35% of the subjects. Eighty-six percent of the individuals with DM1 had mental retardation (MR), most of them moderate or severe MR. ASD was significantly correlated with the DM1 form; the more severe the form of DM1, the higher the frequency of ASD. The frequency of ASD increased with increasing CTG repeat expansions. ASD and/or other neuropsychiatric disorders such as attention deficit hyperactivity disorder, and Tourette's disorder were found in 54% of the total DM1. group. In conclusion, awareness of ASD comorbidity in DM1. is essential. Further studies are warranted to elucidate the molecular etiology causing neurodevelopmental symptoms such as ASD and MR in DM1. (c) 2008 Wiley-Liss, Inc.

Association of the Cannabinoid Receptor Gene (CNR1) With ADHD and Post-Traumatic Stress Disorder

Abstract: Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder affecting some 5-10% of children and 4-5% of adults. The cannabinoid receptor gene (CNR1) is a positional candidate gene due to its location near an identified ADHD linkage peak on chromosome 6, its role in stress and dopamine regulation, its association with other psychiatric disorders that co-occur with ADHD, and its function in learning and memory. We tested SNP variants at the CNR1 gene in two independent samples-an unselected adolescent sample from Northern Finland, and a family-based sample of trios (an ADHD child and their parents). In addition to using the trios for association study, the parents (with and without ADHD) were used as an additional case/control sample of adults for association tests. ADHD and its co-morbid psychiatric disorders were examined. A significant association was detected for a SNP haplotype (C-G) with ADHD (P = 0.008). A sex by genotype interaction was observed as well with this haplotype posing a greater risk in males than females. An association of an alternative SNP haplotype in this gene was found for post-traumatic stress disorder (PTSD) (P = 0.04 for C-A, and P = 0.01 for C-G). These observations require replication, however, they suggest that the CNR1 gene may be a risk factor for ADHD and possibly PTSD, and that this gene warrants further investigation for a role in neuropsychiatric disorders.

Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder

Abstract: Accumulating evidence from animal studies suggests that the corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) neuropeptide systems, contribute to anxiety behavior. To investigate whether polymorphisms in the genes regulating these two systems may alter susceptibility to anxiety disorders in humans, we genotyped 71 single nucleotide polymorphisms (SNPs) in CRH, CRHR1, CRHR2, AVP, AVPR1A, AVPR1B in a German sample from Munich with patients suffering from panic disorder and matched healthy controls (n = 186/n = 299). Significant associations were then replicated in a second German sample with 173 patients with panic disorder and 495 controls. In both samples separately and the combined sample, SNPs within CHRH1 and AVPR1B were nominally associated with panic disorder. We then tested two locus multiplicative and interaction effects of polymorphisms of these two genes on panic disorder. Fifteen SNP pairs showed significant multiplicative effects in both samples. The SNP pair with the most significant association in the combined sample (P = 0.00057), which withstood correction for multiple testing, was rs878886 in CRHR1 and rs28632197 in AVPR1B. Both SNPs are of potential functional relevance as rs878886 is located in the 3' untranslated region of the CRHR1 and rs28632197 leads to an arginine to histidine amino acid exchange at position 364 of AVPR1B which is located in the intracellular C-terminal domain of the receptor. These data suggest that polymorphisms in the AVPR1B and the CRHR1 genes alter the susceptibility to panic disorder.

Evidence That the COMTVal158Met Polymorphism Moderates Sensitivity to Stress in Psychosis : An Experience-Sampling Study

Abstract: Gene–environment interactions involving the catechol-O-methyltransferase Val158Met polymorphism (COMTVal158Met) have been implicated in the causation of psychosis. Evidence from general population studies suggests that Met/Met subjects are sensitive to stress, a trait associated with psychosis. We hypothesized that the Met allele would moderate the effects of stress on negative affect (NA) in controls, and on NA and psychosis in patients with a psychotic disorder. Thirty-one patients with a psychotic disorder and comorbid cannabis misuse and 25 healthy cannabis users were studied with the experience sampling method (ESM), a structured diary technique assessing current context and emotional and psychotic experiences in daily life. A significant interaction between COMTVal158Met genotype and ESM stress in the model of NA was found for patients (interaction χ2 = 7.4, P = 0.02), but not for controls (interaction χ2 = 3.8, P = 0.15). In the model of ESM psychosis, a significant interaction between COMTVal158Met genotype and ESM stress was also apparent (interaction χ2 = 11.6, P < 0.01), with Met/Met patients showing the largest increase in psychotic experiences as well as NA in reaction to ESM stress. The findings suggest that the COMTVal158Met polymorphism moderates affective and psychotic responses to stress in patients with psychosis, providing evidence for gene–environment interaction mechanisms in the formation of psychotic symptoms. © 2007 Wiley-Liss, Inc.

Candidate genes for schizophrenia: a survey of association studies and gene ranking.

Abstract: More than 500 genes have been reported with positive or negative association with schizophrenia. The wealth of this information, along with the complex nature of psychiatric disorders, provides a challenging but also unique opportunity for the investigation of molecular and cellular mechanisms in schizophrenia. In this study, we performed a comprehensive survey of the published association studies collected in the SchizophreniaGene database. We observed over time a strong trend for increases in the number of published reports, the number of studied genes, and the sample size of the studies. We also examined the studies, genes, and sample sizes in different ethnic populations and the distribution of these association studies and their employed markers among these susceptibility genes. We then selected and ranked candidate genes using a combined odds ratio method. The evaluation of this candidate gene set against sets selected by other methods suggested its utility in follow-up association studies and in further bioinformatics analysis. We also examined the functional biases of the selected genes.

Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism.

Abstract: We had previously identified the clock gene D-box binding protein (Dbp) as a potential candidate gene for bipolar disorder and for alcoholism, using a Convergent Functional Genomics (CFG) approach Here we report that mice with a homozygous deletion of DBP have lower locomotor activity, blunted responses to stimulants, and gain less weight over time In response to a chronic stress paradigm, these mice exhibit a diametric switch in these phenotypes DBP knockout mice are also activated by sleep deprivation, similar to bipolar patients, and that activation is prevented by treatment with the mood stabilizer drug valproate Moreover, these mice show increased alcohol intake following exposure to stress Microarray studies of brain and blood reveal a pattern of gene expression changes that may explain the observed phenotypes CFG analysis of the gene expression changes identified a series of novel candidate genes and blood biomarkers for bipolar disorder, alcoholism, and stress reactivity

Genetic influences on the broad spectrum of autism: study of proband-ascertained twins.

Abstract: An investigation of genetic structures underlying autistic traits was performed with samples from twins for which at least one proband had been ascertained as having autism spectrum disorders (ASDs) in our catchment area. In order to adjust for recent concepts of autism, we employed criteria for the broad spectrum of disease and the childhood autism rating scale (CARS) for quantitative assessment. The CARS test was performed on 45 twin pairs (19 monozygotic, 26 dizygotic) detected with a regional routine screening system. The obtained CARS scores were subjected to structural equation modeling (SEM), incorporating sex differences for each causal influence ascertainment correction, using the Mx software. A best fitting model of causal influences on autistic traits measured continuously, incorporating additive genetic (A) and non-shared environmental influences (E), was generated. With this AE model, the estimated heritability was 0.73 for males and 0.87 for females, based on the continuous CARS scores. There was no evidence for the existence of sex-specific genetic influences. Autistic traits were highly heritable in twins with even broad spectrum of autism, corresponding to the results of early studies based on classical autism. Additive genetic factors were more influential in females than males.

A polymorphism at the 3′-untranslated region of the CLOCK gene is associated with adult attention-deficit hyperactivity disorder

Abstract: Attention-deficit hyperactivity disorder (ADHD) is frequently found in childhood and persists in about 50% of cases into adulthood. Several studies demonstrate a relationship between ADHD, circadian rhythmicity and sleeping disturbances in unmedicated ADHD patients. Since ADHD is a very complex disease with a high genetic load involving multiple genes of moderate effect, we hypothesized a link between adult ADHD and genes involved in the circadian timekeeping system. A 3′-UTR polymorphism of the circadian locomotor output cycles protein kaput (CLOCK) gene, rs1801260, has been linked to disturbed sleep patterns, although both the C-allele and more controversially the T-allele have been proposed as risk factors for different measures of evening preference. This study compared self-rating and interview based measures of ADHD psychopathology of 143 subjects with and without ADHD with their rs1801260 genotype to test the hypothesis that ADHD is linked to one of the alleles of the CLOCK polymorphism. The T > C single nucleotide polymorphism rs1801260 was genotyped in DNA isolated from blood samples. The associations between genotype and ADHD-scores were compared using non-parametric ANCOVA with post hoc pairwise comparisons. There was a strong, significant association (P < 0.001) between each of the adult ADHD assessments and the rs1801260 polymorphism with at least one T-mutation being the risk allele. This is the first study suggesting that a polymorphism of a gene within the circadian “clock” mechanism is a direct or linked contributing factor in adult ADHD. © 2007 Wiley-Liss, Inc.

Association of the serotonin transporter polymorphism and obsessive-compulsive disorder: systematic review.

Abstract: We investigated the association between the long (l) and short (s) alleles of the serotonin transporter polymorphism (5-HTTLPR) in the promoter region of the SLC6A4 gene and obsessive-compulsive disorder (OCD) using meta-analysis to combine all published data from case–control and family based association studies (2,283 cases). In stratified meta-analysis we investigated whether age of sample (child and adult), ethnicity (Caucasian and Asian) and study design (case–control and family-based association studies) moderated any association. In the overall meta-analysis we found no evidence of association between genetic variation at the 5-HTTLPR locus and OCD. We did find significant heterogeneity between studies. In the stratified meta-analyses, we demonstrated a significant association between the l-allele and OCD in family-based association studies and in studies involving children and Caucasians. Our meta-analysis suggests the possibility that the l-allele may be associated with OCD in specific OCD subgroups such as childhood-onset OCD and in Caucasians. Further meta-analyses based on individual patient data would be helpful in determining whether age of OCD onset, gender and the presence of comorbid illness (e.g., tics) moderates the relationship between 5-HTTLPR and OCD. © 2008 Wiley-Liss, Inc.

Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis.

Abstract: Depression is common and a major cause of morbidity and mortality and is also known to have serious effects on quality of life. Both clinical and pharmacologic studies have implicated the role of brain-derived neurotrophic factor (BDNF) as a susceptibility locus for the development of mental illness, including depression, bipolar disorder, and schizophrenia. Population-based genetic studies have examined the association between BDNF and a variety of depression outcomes, but the results have not clearly established the role of BDNF in the development of this complex disorder. The aim of this study was to test for associations between two genetic variants in BDNF, Val66Met (rs6265) and -270 C > T, and depression measured in two independent samples. In this analysis we included 3,548 participants from British Women's Heart and Health Study (BWHHS) and 6,836 mothers from Avon Longitudinal Study of Parents and Children (ALSPAC) who had complete data on genotype and depression outcomes. We did not detect any strong evidence of associations between any of the two polymorphisms and indicators of depression in either BWHHS or ALSPAC samples. Further, we carried out a systematic review and meta-analysis of all association studies of these two BDNF polymorphisms and depression. The meta-analysis of Val66Met in depression obtained an overall summary OR of 1.06 (95% CI: 0.89-1.26, P = 0.537) comparing MM with VV genotypes and an OR of 0.97 (95% CI: 0.89-1.05, P = 0.403) comparing MV with VV genotypes. Our findings suggest that BDNF genotype does not exert a major influence on the development of depression.

Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder.

Abstract: We conducted a genome-wide association study of symptom response in an open-label study of a methylphenidate transdermal system (MTS). All DNA extraction and genotyping was conducted at SUNY Upstate Medical University using the Affymetrix Genome-Wide Human SNP Array 6.0. All quality control and association analyses were conducted using the software package PLINK. After data cleaning and quality control, there were 187 subjects (72% (N = 135) male) with mean age 9.2 +/- 2.0 years and 319,722 SNPs available for analysis. The most statistically significant association (rs9627183 and rs11134178; P = 3 x 10(-6)) fell short of the threshold for a genome-wide significant association. The most intriguing association among suggestive findings (rs3792452; P = 2.6 x 10(-5)) was with the metabotropic glutamate receptor 7 gene (GRM7) as it is expressed in brain structures also previously associated with ADHD. Among the 102 available SNPs covering previously studied candidate genes, two SNPs within the norepinephrine transporter gene (NET, SLC6A2) were significant at P < or = 1 x 10(-2). These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate.

Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: a preliminary study.

Abstract: A growing body of literature finds gender differences in ADHD. However, little is known about the causes of these differences. One possibility is that ADHD risk genes have sexually dimorphic effects. We have investigated four ADHD candidate genes (COMT, SLC6A2, MAOA, SLC6A4) for which there is evidence of sexually dimorphic effects. Past neurobiological and genetic studies suggest that COMT, and SLC6A4 variants may have a greater influence on males and that SLC6A2, and MAOA variants may have a greater influence on females. Our results indicate that genetic associations are stronger when stratified by sex and in the same direction as the previous neurobiological studies indicate: associations were stronger in males for COMT, SLC6A4 and stronger in females for SLC6A2, MAOA. Moreover, we found a statistically significant gender effect in the case of COMT (P = 0.007) when we pooled our work with a prior study. In conclusion, we have found some evidence suggesting that the genetic association for these genes with ADHD may be influenced by the sex of the affected individual. Although our results are not fully validated yet, they should motivate further investigation of gender effects in ADHD genetic association studies.

Lithium response and genetic variation in the CREB family of genes.

Abstract: Bipolar disorder (BD) is a severe psychiatric disorder that affects 1% of the population. Recently, there have been many attempts to identify specific genes that are involved in BD; however, the task of finding susceptibility genes is not easy due to the complexity of the disorder. Since lithium (Li) has been used for over 40 years now as an effective prophylactic agent and response to Li treatment seems to be, at least in part, genetically determined, classification according to Li response is a manner through which more homogeneous populations can be obtained for investigation. It has previously been suggested that Li exerts an effect on signal transduction pathways, such as the cyclic adenosine monophosphate (cAMP) pathway. We carried out an association study of BD with CREB1, CREB2 and CREB3 genes, located at ch 2q32.3-q34, 22q13.1 and 9pter-p22.1, respectively. A total of three promoter single nucleotide polymorphisms (SNP), 14 SNPs in the UTR, 6 exonic and 15 intronic SNPs were investigated for their frequency and haplotype distribution in a BD sample of 180 lithium responders and 69 nonresponders and 127 controls using a SNaPshot multiplex reaction from Applied Biosystems, a modified fluorescent single base pair extension procedure. Following correction for multiple testing, our results suggest that the CREB1-1H SNP (G/A change, P < 0.002) and the CREB1-7H SNP (T/C change, P < 0.002) may be associated with BD and/or lithium response.

Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia

Abstract: Functional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n-repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family-based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for “hebephrenia.” Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n-repeat marker of the CNR1 (multi-allelic P = 0.0368). Our hypothesis that an association with the (AAT)n-repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. Schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid-induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia. © 2008 Wiley-Liss, Inc.

Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan.

Abstract: Studies of gene × environment (G × E) interaction in ADHD have previously focused on known risk genes for ADHD and environmentally mediated biological risk. Here we use G × E analysis in the context of a genome-wide association scan to identify novel genes whose effects on ADHD symptoms and comorbid conduct disorder are moderated by high maternal expressed emotion (EE). SNPs (600,000) were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. ADHD symptom severity and comorbid conduct disorder was measured using the Parental Account of Childhood Symptoms interview. Maternal criticism and warmth (i.e., EE) were coded by independent observers on comments made during the interview. No G × E interactions reached genome-wide significance. Nominal effects were found both with and without genetic main effects. For those with genetic main effects 36 uncorrected interaction P-values were <10−5 implicating both novel genes as well as some previously supported candidates. These were found equally often for all of the interactions being investigated. The observed interactions in SLC1A1 and NRG3 SNPs represent reasonable candidate genes for further investigation given their previous association with several psychiatric illnesses. We find evidence for the role of EE in moderating the effects of genes on ADHD severity and comorbid conduct disorder, implicating both novel and established candidates. These findings need replicating in larger independent samples.