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Richard Anney,
Lambertus Klei,
Dalila Pinto,
Joana Almeida,
Elena Bacchelli,
Gillian Baird,
Nadia Bolshakova,
Sven Bölte,
Patrick F Bolton,
Thomas Bourgeron, [......],
Edwin H Cook,
Louise Gallagher,
Michael Gill,
Joachim Hallmayer,
Andrew D Paterson,
James S Sutcliffe,
Peter Szatmari,
Veronica J Vieland,
Hakon Hakonarson,
Bernie Devlin
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ABSTRACT: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Human Molecular Genetics 07/2012; 21(21):4781-92. · 7.64 Impact Factor
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Jillian P Casey,
Tiago Magalhaes,
Judith M Conroy,
Regina Regan,
Naisha Shah,
Richard Anney,
Denis C Shields,
Brett S Abrahams,
Joana Almeida,
Elena Bacchelli, [......],
Stephen W Scherer,
James S Sutcliffe,
Peter Szatmari,
Veronica J Vieland,
Ellen M Wijsman,
Andrew Green,
Michael Gill,
Louise Gallagher,
Astrid Vicente,
Sean Ennis
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ABSTRACT: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Human Genetics 10/2011; 131(4):565-79. · 5.07 Impact Factor
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Keun-Ah Cheon,
Young-Shin Kim,
Se-Hong Oh,
Sung-Yeon Park,
Hyo-Woon Yoon,
John Herrington,
Aarti Nair,
Yun-Joo Koh,
Dong-Pyo Jang,
Young-Bo Kim, Bennett L Leventhal,
Zang-Hee Cho,
F Xavier Castellanos,
Robert T Schultz
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ABSTRACT: Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the key thalamic relay nuclei and cortico-thalamic connectivity in the pathophysiology of autism. Accordingly, we aimed to focus on evaluating the integrity of the thalamic radiation and sought to replicate prior white matter findings in Korean boys with high-functioning autism spectrum disorders (ASD) using Diffusion Tensor Imaging (DTI).
We compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 17 boys with ASD and 17 typically developing controls in the anterior thalamic radiation (ATR), superior thalamic radiation (STR), posterior thalamic radiation (PTR), corpus callosum (CC), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF).
The two groups were group-matched on age, IQ, handedness and head circumference. In whole-brain voxel-wise analyses, FA was significantly reduced and MD was significantly increased in the right ATR, CC, and left UF in subjects with ASD (p<0.05, corrected). We found significantly lower FA in right and left ATR, CC, left UF and right and left ILF and significantly higher MD values of the CC in the ASD group in region of interest-based analyses. We also observed significantly higher RD values of right and left ATR, CC, left UF, left ILF in subjects with ASD compared to typically developing boys and significantly lower AD values of both ILF. Right ATR and right UF FA was significantly negatively correlated with total SRS score within the ASD group (r=-.56, p=.02).
Our preliminary findings support evidence implicating disturbances in the thalamo-frontal connections in autism. These findings highlight the role of hypoconnectivity between the frontal cortex and thalamus in ASD.
Brain research 08/2011; 1417:77-86. · 2.46 Impact Factor
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Young Shin Kim, Bennett L Leventhal,
Yun-Joo Koh,
Eric Fombonne,
Eugene Laska,
Eun-Chung Lim,
Keun-Ah Cheon,
Soo-Jeong Kim,
Young-Key Kim,
Hyunkyung Lee,
Dong-Ho Song,
Roy Richard Grinker
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ABSTRACT: Experts disagree about the causes and significance of the recent increases in the prevalence of autism spectrum disorders (ASDs). Limited data on population base rates contribute to this uncertainty. Using a population-based sample, the authors sought to estimate the prevalence and describe the clinical characteristics of ASDs in school-age children.
The target population was all 7- to 12-year-old children (N=55,266) in a South Korean community; the study used a high-probability group from special education schools and a disability registry and a low-probability, general-population sample from regular schools. To identify cases, the authors used the Autism Spectrum Screening Questionnaire for systematic, multi-informant screening. Parents of children who screened positive were offered comprehensive assessments using standardized diagnostic procedures.
The prevalence of ASDs was estimated to be 2.64% (95% CI=1.91-3.37), with 1.89% (95% CI=1.43-2.36) in the general-population sample and 0.75% (95% CI=0.58-0.93) in the high-probability group. ASD characteristics differed between the two groups: the male-to-female ratios were 2.5:1 and 5.1:1 in the general population sample and high-probability group, respectively, and the ratios of autistic disorders to other ASD subtypes were 1:2.6 and 2.6:1, respectively; 12% in the general-population sample had superior IQs, compared with 7% in the high-probability group; and 16% in the general-population sample had intellectual disability, compared with 59% in the high-probability group.
Two-thirds of ASD cases in the overall sample were in the mainstream school population, undiagnosed and untreated. These findings suggest that rigorous screening and comprehensive population coverage are necessary to produce more accurate ASD prevalence estimates and underscore the need for better detection, assessment, and services.
American Journal of Psychiatry 05/2011; 168(9):904-12. · 12.54 Impact Factor
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Psychiatric genetics 11/2010; 21(4):212-3. · 2.33 Impact Factor
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Richard Anney,
Lambertus Klei,
Dalila Pinto,
Regina Regan,
Judith Conroy,
Tiago R Magalhaes,
Catarina Correia,
Brett S Abrahams,
Nuala Sykes,
Alistair T Pagnamenta, [......],
Gerard D Schellenberg,
Stephen W Scherer,
James S Sutcliffe,
Peter Szatmari,
Astrid M Vicente,
Veronica J Vieland,
Ellen M Wijsman,
Bernie Devlin,
Sean Ennis,
Joachim Hallmayer
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ABSTRACT: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Human Molecular Genetics 10/2010; 19(20):4072-82. · 7.64 Impact Factor
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Dalila Pinto,
Alistair T Pagnamenta,
Lambertus Klei,
Richard Anney,
Daniele Merico,
Regina Regan,
Judith Conroy,
Tiago R Magalhaes,
Catarina Correia,
Brett S Abrahams, [......],
Andrew D Paterson,
Margaret A Pericak-Vance,
Gerard D Schellenberg,
Peter Szatmari,
Astrid M Vicente,
Veronica J Vieland,
Ellen M Wijsman,
Stephen W Scherer,
James S Sutcliffe,
Catalina Betancur
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[hide abstract]
ABSTRACT: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Nature 07/2010; 466(7304):368-72. · 36.28 Impact Factor
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ABSTRACT: To determine the effect of serotonin transporter polymorphism promoter region (5-HTTPLR) genotypic variation (low, intermediate, and high expression groups) on response to escitalopram treatment of children and adolescents with autism spectrum disorders (ASDs).
The study used a forced titration, open label design, with genotype blind until study completion. Participants were children and adolescents aged 4-17 years of age with a confirmed ASD (autistic disorder, Asperger's disorder, or pervasive developmental disorder, not otherwise specified).
There was an interaction between genotype group and time on the Aberrant Behavior Checklist (ABC) Irritability Subscale (primary outcome variable) (linear maximum marginal likelihood estimation=-4.84, Z=-2.89, SE=1.67, P=0.004). Examination of baseline to last visit revealed that a genotype grouping based on a previous study of platelet 5-HT uptake revealed less response in the genotype group that had S/S genotype for 5-HTTLPR and did not have a diplotype in intron 1 previously shown to be associated with increased platelet 5-HT uptake.
This genotype-blind, prospective pharmacogenetic study found the group of subjects with associated with the lowest platelet 5-HT uptake from previous study had the smallest reduction in ABC-Irritability scores after open label treatment with escitalopram. Replication is necessary to confirm these findings.
Autism Research 12/2009; 3(1):1-7. · 3.69 Impact Factor
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Lauren A. Weiss,
Dan E. Arking,
Mark J. Daly,
Aravinda Chakravarti,
Camille W. Brune,
Kristen West,
Ashley O|[rsquo]|Connor,
Gina Hilton,
Rebecca L. Tomlinson,
Andrew B. West, [......],
Alison Schonwald,
Esau Simmons,
Leonard A. Rappaport,
Julie Gauthier,
Laurent Mottron,
Ridha Joober,
Guy Rouleau,
Karola Rehnstrom,
Lennart von Wendt,
Leena Peltonen
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ABSTRACT: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success
Nature 10/2009; 461(7265):802-808. · 36.28 Impact Factor
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ABSTRACT: To illustrate time trends and trajectories of bullying and identify demographic predictors of bullying.
A prospective study of 1666 seventh- and eighth-grade students from two Korean middle schools was conducted between 2000 and 2001. Using the Korean-Peer Nomination Inventory, bullying was categorized into four groups: victim, perpetrator, victim-perpetrator, and neither.
Only the prevalence of male victims significantly decreased over the course of the study. Most students uninvolved in bullying at baseline remained so over the study period. In all, 52-58% of baseline victims and perpetrators and 74% of victim-perpetrators continued to be involved in bullying. Significantly more boys were involved with bullying than girls; individual stability of bullying behavior did not differ by gender. Shorter, heavier boys and those from lower SES, whose fathers had lower educational levels or whose mothers had higher educational levels, as well as shorter girls from Seoul or non-intact families, were at an increased risk for bullying.
Except for a modest decline in the number of male victims, participation in bullying (especially by victim-perpetrators) is stable over time. Along with disadvantaged background, distinct demographic profiles of bullying involvement by sex and bullying groups emerged, allowing early identification of bullying and targeting intervention and prevention.
Journal of Adolescent Health 10/2009; 45(4):360-7. · 3.33 Impact Factor
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ABSTRACT: There is increasing consensus that disruptive behavior disorders and syndromes (DBDs) are identifiable in preschool children. There is also concomitant recognition of the limitations of the current DBD nosology for distinguishing disruptive behavior symptoms from the normative misbehavior of early childhood. In particular, there appears to be substantial insensitivity to heterotypic manifestations of this developmental period and problems in identifying meaningful heterogeneity. As a result, the developmental basis for much of the current nosology may be called into question. To address these and other critical issues, this paper reviews the foundational elements of clinical and developmental science pertinent to developmental differentiation of disruptive behavior in the preschool period as paradigmatic for developmental specification across the lifespan and generates an agenda for future research. We begin by reviewing evidence of the validity of DBDs in preschool children. This is followed by an outline of key developmental concepts and a review of the corollary evidence from developmental science. These provide a basis for conceptualizing disruptive behavior in reference to developmental deviation in four core dimensions hypothesized to mark the core features of disruptive behavior syndromes. Finally, we propose a program of research to establish an empirical basis for determining the incremental utility of a developmentally specified nosology. Central to this approach is a contention that the benefits of developmental specification are extensive and outweigh any disadvantages. This is because a developmentally specified approach holds substantial promise for increasing sensitivity and specificity for differentiating disruptive behavior from normative misbehavior and from other related syndromes as well as for improving prediction. Further, more precisely defined, developmentally based phenotypes are likely to elucidate distinct mechanisms within translational studies and to serve as a catalyst for the generation of novel treatments.
Journal of Child Psychology and Psychiatry 10/2009; 51(1):3-22. · 4.28 Impact Factor
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Epidemiology (Cambridge, Mass.) 08/2009; 20(4):622-3; author reply 623-4. · 5.51 Impact Factor
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ABSTRACT: The dopamine transporter locus (DAT1) has been studied as a risk factor for attention-deficit/hyperactivity disorder (ADHD) and in pharmacogenetic studies of stimulant response. Several prospective studies have reported an association between the homozygous 9 repeat allele of the DAT1 3' untranslated region (UTR) variable number tandem repeat (VNTR) (DAT1 3') and decreased efficacy of methylphenidate (MPH). We hypothesized that children with the 9/9 genotype would display higher rates of specific stimulant side effects. Data on adverse events and DAT1 3' genotypes were combined from two, double-blind, placebo-controlled, crossover studies of MPH conducted in child psychiatric outpatient clinics in Montreal and Washington, D.C. There were 177 participants, 5-16 years old (mean age = 8.99, standard deviation [SD] = 2), with ADHD. Parents completed the Stimulant Side Effect Scale (SERS) after a week of placebo and a week of MPH treatment. Principal components analysis of the SERS resulted in three factors: Emotionality, Somatic Complaints, and Over-focused. Children with the 9/9 genotype displayed higher scores on the Emotionality factor during placebo than children with the 9/10 and the 10/10 genotype, and their Emotionality scores increased further during MPH treatment (F[2,151] = 3.24, p < 0.05). Children with the 10/10 genotype displayed a significant increase in Somatic Complaint factor scores during MPH treatment relative to the other genotype groups (F[2,150] = 3.4, p < 0.05). These data provide suggestive evidence that DAT1 variants are differentially associated with specific stimulant side effects. Children with the 9/10 genotype displayed less severe stimulant side-effect ratings than either of the homozygous groups, who each displayed increased susceptibility to different types of adverse events. Preliminary evidence suggests that pharmacogenetic analysis using DAT1 variants shows promise for identifying individuals at increased or decreased risk for poor tolerability.
Journal of child and adolescent psychopharmacology 06/2009; 19(3):233-9. · 2.59 Impact Factor
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ABSTRACT: This study examines the independent impact of bullying on suicide risk. Bullying was assessed by peer nomination in a prospective study of 1,655 7th and 8th grade Korean students, and suicide by youth self-report. Odds Ratios (ORs) of bullying for suicidal risks were computed, controlling for other suicide risk factors. Victim-Perpetrators and female Victims at baseline showed increased risk for persistent suicidality (OR: 2.4-9.8). Male Incident Victims exhibited increased risk for suicidal behaviors and ideations (OR = 4.4, 3.6). Female Persistent Perpetrators exhibited increased risks for suicidal behaviors; male Incident Perpetrators had increased risk for suicidal ideations (OR = 2.7, 2.3). Baseline-only male Victim-Perpetrators showed increased risk for suicidal ideations. (OR = 6.4). Bullying independently increased suicide risks.
Archives of suicide research: official journal of the International Academy for Suicide Research 02/2009; 13(1):15-30.
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ABSTRACT: To examine the validity of the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS), a new observational method for assessing preschool disruptive behavior.
A total of 327 behaviorally heterogeneous preschoolers from low-income environments comprised the validation sample. Parent and teacher reports were used to identify children with clinically significant disruptive behavior. The DB-DOS assessed observed disruptive behavior in two domains, problems in Behavioral Regulation and Anger Modulation, across three interactional contexts: Examiner Engaged, Examiner Busy, and Parent. Convergent and divergent validity of the DB-DOS were tested in relation to parent and teacher reports and independently observed behavior. Clinical validity was tested in terms of criterion and incremental validity of the DB-DOS for discriminating disruptive behavior status and impairment, concurrently and longitudinally.
DB-DOS scores were significantly associated with reported and independently observed behavior in a theoretically meaningful fashion. Scores from both DB-DOS domains and each of the three DB-DOS contexts contributed uniquely to discrimination of disruptive behavior status, concurrently and predictively. Observed behavior on the DB-DOS also contributed incrementally to prediction of impairment over time, beyond variance explained by meeting DSM-IV disruptive behavior disorder symptom criteria based on parent/teacher report.
The multidomain, multicontext approach of the DB-DOS is a valid method for direct assessment of preschool disruptive behavior. This approach shows promise for enhancing accurate identification of clinically significant disruptive behavior in young children and for characterizing subtypes in a manner that can directly inform etiological and intervention research.
Journal of the American Academy of Child and Adolescent Psychiatry 07/2008; 47(6):632-41. · 4.98 Impact Factor
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Lauren S Wakschlag,
Carri Hill,
Alice S Carter,
Barbara Danis,
Helen L Egger,
Kate Keenan, Bennett L Leventhal,
Domenic Cicchetti,
Katie Maskowitz,
James Burns,
Margaret J Briggs-Gowan
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ABSTRACT: To examine the reliability of the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS), a new observational method for assessing preschool disruptive behavior.
The DB-DOS is a structured clinic-based assessment designed to elicit clinically salient behaviors relevant to the diagnosis of disruptive behavior in preschoolers. Child behavior is assessed in three interactional contexts that vary by partner (parent versus examiner) and level of support provided. Twenty-one disruptive behaviors are coded within two domains: problems in Behavioral Regulation and problems in Anger Modulation. A total of 364 referred and nonreferred preschoolers participated: interrater reliability and internal consistency were assessed on a primary sample (n = 335) and test-retest reliability was assessed in a separate sample (n = 29).
The DB-DOS demonstrated good interrater and test-retest reliability. Confirmatory factor analysis demonstrated an excellent fit of the DB-DOS multidomain model of disruptive behavior.
The DB-DOS is a reliable observational tool for clinic-based assessment of preschool disruptive behavior. This standardized assessment method holds promise for advancing developmentally sensitive characterization of preschool psychopathology.
Journal of the American Academy of Child and Adolescent Psychiatry 07/2008; 47(6):622-31. · 4.98 Impact Factor
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ABSTRACT: Reports identified the neuronal glutamate transporter gene, SLC1A1 (OMIM 133550, chromosome 9p24), as a positional and functional candidate gene for obsessive-compulsive disorder (OCD). The presence of obsessions and compulsions similar to OCD in autism, the identification of this region in a genome-wide linkage analysis of individuals with autism spectrum disorders (ASDs), and the hypothesized role of glutamate in ASDs make SLC1A1 a candidate gene for ASD as well. To test for association between SLC1A1 and autism, we typed three single nucleotide polymorphisms (SNPs, rs301430, rs301979, rs301434) previously associated with OCD in 86 strictly defined trios with autism. Family-Based Association Tests (FBAT) with additive and recessive models were used to check for association. Additionally, an rs301430-rs301979 haplotype identified for OCD was investigated. FBAT revealed nominally significant association between autism and one SNP under a recessive model. The G allele of rs301979 was undertransmitted (equivalent to overtransmission of the C allele under a dominant model) to individuals with autism (Z=-2.47, P=0.01). The G allele was also undertransmitted in the T-G haplotype under the recessive model (Z=-2.41, P=0.02). Both findings were also observed in the male-only sample. However, they did not withstand correction for multiple comparisons.
Autism Research 05/2008; 1(2):108-13. · 3.69 Impact Factor
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ABSTRACT: Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (K(m), p=0.005) and 5-HT uptake rate (V(max), p=0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p=0.046). These initial studies of indices of the 5-HT system with several single-nucleotide polymorphisms at loci in this system generate hypotheses for testing in other samples.
Neuropsychopharmacology 02/2008; 33(2):353-60. · 7.99 Impact Factor
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ABSTRACT: Attaining a developmentally sensitive nosology for preschool disruptive behavior requires characterization of the features that distinguish it from the normative misbehavior of this developmental period. We hypothesize that quality of behavior and its pervasiveness across contexts are critical dimensions for clinical discrimination in young children and propose that structured diagnostic observation provides a systematic method for their identification. We use the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS) to examine whether: (a) observed quality and pervasiveness of behavior distinguishes preschoolers with clinically concerning disruptive behavior from typically developing preschoolers, and (b) observed pattern of clinically salient behavior predicts impairment above and beyond maternal report of behavioral frequency.
Participants are a behaviorally heterogeneous sample of preschoolers (N = 327). Diagnostic methods developed for clinical assessment of preschoolers were used to classify children as (a) Non-Disruptive, (b) Sub-Clinical, or (c) Disruptive. Child behavior was coded based on interactions with parent and examiner during the DB-DOS.
Quality and pervasiveness of observed behaviors during the DB-DOS significantly distinguished the three behavioral groups. Discriminative utility varied depending on the comparison. With few exceptions, clinically concerning patterns on the DB-DOS added significant incremental utility in predicting impairment.
Observed patterns of clinically salient behavior show promise for advancing developmentally-informed characterization of disruptive behavior within the preschool period.
Journal of Child Psychology and Psychiatry 11/2007; 48(10):976-87. · 4.28 Impact Factor
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Gregory L Hanna,
Jeremy Veenstra-Vanderweele,
Nancy J Cox,
Michelle Van Etten,
Daniel J Fischer,
Joseph A Himle,
Nancy Chiu Bivens,
Xiaolin Wu,
Cheryl A Roe,
Kathleen A Hennessy,
Diane E Dickel, Bennett L Leventhal,
Edwin H Cook
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ABSTRACT: The goal of this study was to identify chromosomal regions likely to contain susceptibility loci for obsessive-compulsive disorder (OCD).
We conducted a genome-wide linkage scan, with average marker spacing less than 10 centimorgans (cM), in 121 subjects from 26 families ascertained through probands with early-onset OCD. Best estimate lifetime psychiatric diagnoses were based on semistructured interviews and all other available sources of information. Parametric and nonparametric linkage analyses were conducted with GENEHUNTER+ and Allegro. Family-based association analyses were done using 35 single nucleotide polymorphisms (SNPs) in the 10p15 region.
The maximum nonparametric log of odds (NLOD) score was 2.43 on chromosome 10p15 at position 4.37. When data from our first genome scan were added to data from this scan, the maximum NLOD score in the 10p15 region was 1.79. Association was detected on 10p15 with three adjacent SNPs, including the amino acid variant rs2271275 in the 3' region of adenosine deaminase acting on RNA 3 (ADAR3) (p < .05).
The results provide suggestive evidence for linkage on chromosome 10p15. Evidence for association in the linkage region was found with three markers in the 3' end of ADAR3. Limitations include the lack of significant linkage and association findings when corrected for multiple testing.
Biological Psychiatry 11/2007; 62(8):856-62. · 8.28 Impact Factor
