Censoring distances based on labeled cortical distance maps in cortical morphometry.

It has been demonstrated that shape differences in cortical structures may be manifested in neuropsychiatric disorders. Such morphometric differences can be measured by labeled cortical distance mapping (LCDM) which characterizes the morphometry of the laminar cortical mantle of cortical structures. LCDM data consist of signed/labeled distances of gray matter (GM) voxels with respect to GM/white matter (WM) surface. Volumes and other summary measures for each subject and the pooled distances can help determine the morphometric differences between diagnostic groups, however they do not reveal all the morphometric information contained in LCDM distances. To extract more information from LCDM data, censoring of the pooled distances is introduced for each diagnostic group where the range of LCDM distances is partitioned at a fixed increment size; and at each censoring step, the distances not exceeding the censoring distance are kept. Censored LCDM distances inherit the advantages of the pooled distances but also provide information about the location of morphometric differences which cannot be obtained from the pooled distances. However, at each step, the censored distances aggregate, which might confound the results. The influence of data aggregation is investigated with an extensive Monte Carlo simulation analysis and it is demonstrated that this influence is negligible. As an illustrative example, GM of ventral medial prefrontal cortices (VMPFCs) of subjects with major depressive disorder (MDD), subjects at high risk (HR) of MDD, and healthy control (Ctrl) subjects are used. A significant reduction in laminar thickness of the VMPFC in MDD and HR subjects is observed compared to Ctrl subjects. Moreover, the GM LCDM distances (i.e., locations with respect to the GM/WM surface) for which these differences start to occur are determined. The methodology is also applicable to LCDM-based morphometric measures of other cortical structures affected by disease.

Social and non-social cueing of visuospatial attention in autism and typical development.

Three experiments explored attention to eye gaze, which is incompletely understood in typical development and is hypothesized to be disrupted in autism. Experiment 1 (n = 26 typical adults) involved covert orienting to box, arrow, and gaze cues at two probabilities and cue-target times to test whether reorienting for gaze is endogenous, exogenous, or unique; experiment 2 (total n = 80: male and female children and adults) studied age and sex effects on gaze cueing. Gaze cueing appears endogenous and may strengthen in typical development. Experiment 3 tested exogenous, endogenous, and gaze-based orienting in 25 typical and 27 Autistic Spectrum Disorder (ASD) children. ASD children made more saccades, slowing their reaction times; however, exogenous and endogenous orienting, including gaze cueing, appear intact in ASD.

Family-based genome-wide association scan of attention-deficit/hyperactivity disorder.

OBJECTIVE: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD. METHOD: Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. RESULTS: Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. CONCLUSIONS: We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.

ADH1B*3 and response to alcohol in African-Americans.

BACKGROUND: Variations in the alleles for the alcohol-metabolizing enzymes have been shown to influence risk for alcohol dependence. One variant, ADH1B*3, is observed almost exclusively in populations of African ancestry and has been shown to be associated with reduced rates of alcohol dependence. We conducted an alcohol challenge study to test whether ADH1B*3 is associated with differences in subjective and physiological response to alcohol. METHOD: We administered a moderate dose of alcohol (0.72 g/kg for males, 0.65 g/kg for females) to a sample of African-American young adults (n = 91; ages 21 to 26). Participants were genotyped for ADH1B, as well as additional polymorphisms that might contribute to alcohol response. Breath alcohol concentration, self-reported sedation and stimulation, and pulse rate were assessed prior to alcohol administration and for 2.5 hours following administration. RESULTS: ADH1B*3 was associated with higher levels of sedation and a sharper increase in pulse rate immediately following alcohol consumption. CONCLUSIONS: These findings suggest that the lower rates of alcohol dependence in those with ADH1B*3 alleles may be because of differences in alcohol response, particularly increased sedation.

Sex and age differences in attention-deficit/hyperactivity disorder symptoms and diagnoses: implications for DSM-V and ICD-11.

OBJECTIVE: To examine gender and age differences in attention-deficit/hyperactivity disorder (ADHD) symptom endorsement in a large community-based sample. METHOD: Families with four or more full siblings ascertained from Missouri birth records completed telephone interviews regarding lifetime DSM-IV ADHD symptoms and the Strengths and Weaknesses of ADHD-Symptoms and Normal-behavior (SWAN) questionnaire for current ADHD symptoms. Complete data were available for 9,380 subjects aged 7 through 29 years. Lifetime and current DSM-IV-like ADHD diagnoses were assigned by the DSM-IV symptom criteria. Linear regression was used to examine sex and age effects on SWAN ADHD symptom scores. Logistic regression was used to examine sex and age effects on specific ADHD diagnoses. Fractional polynomial graphs were used to examine ADHD symptom count variations across age. RESULTS: Overall prevalence of current DSM-IV-like ADHD was 9.2% with a male:female ratio of 2.28:1. The prevalence of DSM-IV-like ADHD was highest in children. Gender differences in DSM-IV-like ADHD subtype prevalences were highest in adolescents. On average, individuals with lifetime DSM-IV-like ADHD diagnoses had elevated current ADHD symptoms even as adolescents or adults. CONCLUSIONS: Lower male:female ratios than reported in some clinic-based studies suggest that females are underdiagnosed in the community. Although they may no longer meet the full symptom criteria, young adults with a history of lifetime DSM-IV-like ADHD maintain higher levels of ADHD symptoms compared with the general population. The use of age-specific diagnostic criteria should be considered for DSM-V and ICD-11.

Effects of child maltreatment and inherited liability on antisocial development: an official records study.

OBJECTIVE: Evidence is steadily accumulating that a preventable environmental hazard, child maltreatment, exerts causal influences on the development of long-standing patterns of antisocial behavior in humans. The relationship between child maltreatment and antisocial outcome, however, has never previously been tested in a large-scale study in which official reports (rather than family member reports) of child abuse and neglect were incorporated, and genetic influences comprehensively controlled for. METHOD: We cross-referenced official report data on child maltreatment from the Missouri Division of Social Services (DSS) with behavioral data from 4,432 epidemiologically ascertained Missouri twins from the Missouri Twin Registry (MOTWIN). We performed a similar procedure for a clinically ascertained sample of singleton children ascertained from families affected by alcohol dependence participating in the Collaborative Study on the Genetics of Alcoholism (COGA; n = 428) to determine whether associations observed in the general population held true in an "enriched" sample at combined inherited and environmental risk for antisocial development. RESULTS: For both the twin and clinical samples, the additive effects (not interactive effects) of maltreatment and inherited liability on antisocial development were confirmed and were highly statistically significant. CONCLUSIONS: Child maltreatment exhibited causal influence on antisocial outcome when controlling for inherited liability in both the general population and in a clinically ascertained sample. Official report maltreatment data represents a critical resource for resolving competing hypotheses on genetic and environmental causation of child psychopathology, and for assessing intervention outcomes in efforts to prevent antisocial development.

Linkage analysis of alcohol dependence symptoms in the community.

BACKGROUND: We have previously identified suggestive linkage for alcohol consumption in a community-based sample of Australian adults. In this companion paper, we explore the strength of genetic linkage signals for alcohol dependence symptoms. METHODS: An alcohol dependence symptom score, based on DSM-IIIR and DSM-IV criteria, was examined. Twins and their nontwin siblings (1,654 males, 2,518 females), aged 21 to 81 years, were interviewed, with 803 individuals interviewed on 2 occasions, approximately 10 years apart. Linkage analyses were conducted on datasets compiled to maximize data collected at either the younger or the older age. In addition, linkage was compared between full samples and truncated samples that excluded the lightest drinkers (approximately 10% of the sample). RESULTS: Suggestive peaks on chromosome 5p (LODs >2.2) were found in a region previously identified in alcohol linkage studies using clinical populations. Linkage signal strength was found to vary between full and truncated samples and when samples differed only on the collection age for a sample subset. CONCLUSIONS: The results support the finding that large community samples can be informative in the study of alcohol-related traits.

Alcohol consumption indices of genetic risk for alcohol dependence.

BACKGROUND: Previous research has reported a significant genetic correlation between heaviness of alcohol consumption and alcohol dependence (AD), but this association might be driven by the influence of AD on consumption rather than the reverse. We test the genetic overlap between AD symptoms and a heaviness of consumption measure among individuals who do not have AD. A high genetic correlation between these measures would suggest that a continuous measure of consumption may have a useful role in the discovery of genes contributing to dependence risk. METHODS: Factor analysis of five alcohol use measures was used to create a measure of heaviness of alcohol consumption. Quantitative genetic analyses of interview data from the 1989 Australian Twin Panel (n = 6257 individuals; M = 29.9 years) assessed the genetic overlap between heaviness of consumption, DSM-IV AD symptoms, DSM-IV AD symptom clustering, and DSM-IV alcohol abuse. RESULTS: Genetic influences accounted for 30%-51% of the variance in the alcohol measures and genetic correlations were .90 or higher for all measures, with the correlation between consumption and dependence symptoms among nondependent individuals estimated at .97 (95% confidence interval: .80-1.00). CONCLUSIONS: Heaviness of consumption and AD symptoms have a high degree of genetic overlap even among nondependent individuals in the general population, implying that genetic influences on dependence risk in the general population are acting to a considerable degree through heaviness of use and that quantitative measures of consumption will likely have a useful role in the identification of genes contributing to AD.

Developing a quantitative measure of alcohol consumption for genomic studies on prospective cohorts.

OBJECTIVE: The purpose of this study was to develop a quantitative measure of alcohol consumption for gene-mapping studies. METHOD: Using a sample of 3,787 young-adult twin women and an independent sample of 489 men and women from a college drinking study, we developed an alcohol-consumption factor score indexed by (1) maximum typical consumption (log-transformed quantity frequency [LQNTFRQ]), (2) maximum drinks in a 24-hours period (LMAXALC), (3) frequency of drinking five or more drinks per day (FIVE), and (4) frequency of drinking to intoxication (INTOX). We tested (1) for factorial and psychometric equivalence across samples and genders; (2) for construct validity and its equivalence, across samples and genders, using measures of tobacco and cannabis use and family history of alcoholism; and (3) to determine the heritability of the alcohol-consumption factor score using a genetic psychometric model. RESULTS: A single-factor model fit well with factor loadings ranging from .60 to .90. With rare exception, we found support for measurement invariance across the two samples and across genders. Measures of nicotine and cannabis use as well as family history of alcoholism were associated, to a similar extent across samples and genders, with the underlying alcohol-consumption factor. Psychometric twin modeling revealed that each of the alcohol-consumption measures (h2=34%-47%) and the underlying factor score (h2=50%) were heritable, with the remainder of the variance attributable to individual-specific environmental factors. This moderately heritable alcohol-consumption factor also accounted for a majority of the genetic variance in LQNTFRQ, LMAXALC, FIVE, and INTOX. CONCLUSIONS: Quantitative measures of alcohol consumption with the favorable attributes of measurement invariance, construct validity, and moderate heritability can greatly enhance future gene-mapping efforts, supplementing information afforded by conventional diagnostic measures of alcohol abuse/dependence.

Simple identification of complex ADHD subtypes using current symptom counts.

OBJECTIVE: New attention-deficit/hyperactivity disorder (ADHD) subtypes identified through latent class analysis have been recently proposed. Here, we assess the accuracy of simple rules based on symptom counts for the assignment of youths to clinically relevant population-derived ADHD subtypes: severe inattentive (SI) and severe combined (SC). METHOD: Data from 9,675 twins and siblings from Missouri and Australia aged 7 to 19 years were analyzed using continuous and categorical models of ADHD symptoms using principal components analysis and subtyping by DSM-IV and by latent class criteria. Cut points were derived for classifying SI and SC subtypes by positive predictive value, negative predictive value, percent positive agreement, and Matthew coefficient of agreement. RESULTS: Principal components analysis suggested two underlying factors: total number of symptoms and symptom type, with SI and SC latent class subtypes clearly mapping to distinct areas on a plot of these factors. Having six or more total symptoms and fewer than three hyperactive-impulsive symptoms accurately predicts the latent class SI subtype. The latent class SC subtype was best identified by 11 or more total symptoms and 4 or more hyperactive-impulsive. The DSM-IV ADHD subtype criteria accurately identified the SC subtype but only poorly for the SI subtype. CONCLUSIONS: Symptom counts criteria allow the simple and accurate identification of subjects with severe ADHD subtypes defined by latent class analysis. Such simple symptom counts corresponding to screening cut points selected latent class-derived SI subtype subjects with greater precision than DSM-IV criteria.

Can we identify genes for alcohol consumption in samples ascertained for heterogeneous purposes?

BACKGROUND: Previous studies have identified evidence of genetic influence on alcohol use in samples selected to be informative for alcoholism research. However, there are a growing number of genome-wide association studies (GWAS) using samples unselected for alcohol consumption (i.e., selected on other traits and forms of psychopathology), which nevertheless assess consumption as a risk factor. Is it reasonable to expect that genes contributing to variation in alcohol consumption can be identified in such samples? METHODS: An exploratory approach was taken to determine whether linkage analyses for heaviness of alcohol consumption, using a sample collected for heterogeneous purposes, could replicate previous findings. Quantity and frequency measures of consumption were collected in telephone interviews from community samples. These measures, and genotyping, were available for 5,441 individuals (5,067 quasi-independent sibling pairs). For 1,533 of these individuals, data were collected on 2 occasions, about 8.2 years apart, providing 2 datasets that maximize data collected at either a younger or an older age. Analyses were conducted to address the question of whether age and heavier levels of alcohol consumption effects outcome. Linkage results were compared in the younger and older full samples, and with samples in which approximately 10, 20, and 40 of drinkers from the lower end of the distribution of alcohol consumption were dropped. RESULTS: Linkage peaks varied for the age differentiated samples and for percentage of light drinkers retained. Larger peaks (LOD scores >2.0) were typically found in regions previously identified in linkage studies and/or containing proposed candidate genes for alcoholism including AGT, CARTPT, OPRD1, PIK3R1, and PDYN. CONCLUSIONS: The results suggest that GWAS assessing alcohol consumption as a covariate for other conditions will have some success in identifying genes contributing to consumption-related variation. However, sample characteristics, such as participant age, and trait distribution, may have substantial effects on the strength of the genetic signal. These results can inform forthcoming GWAS where the same restrictions apply.

Developmental course of autistic social impairment in males.

Recent research has suggested that autistic social impairment (ASI) is continuously distributed in nature and that subtle autistic-like social impairments aggregate in the family members of children with pervasive developmental disorders (PDDs). This study examined the longitudinal course of quantitatively characterized ASI in 3- to 18-year-old boys with and without PDD. We obtained assessments of 95 epidemiologically ascertained male-male twin pairs and a clinical sample of 95 affected children using the Social Responsiveness Scale (SRS), at two time points, spaced 1-5 years apart. Longitudinal course was examined as a function of age, familial loading for PDD, and autistic severity at baseline. Interindividual variation in SRS scores was highly preserved over time, with test-retest correlation of 0.90 for the entire sample. SRS scores exhibited modest general improvement over the study period; individual trajectories varied as a function of severity at baseline and were highly familial. Quantitative measurements of ASI reflect heritable traitlike characteristics. Such measurements can serve as reliable indices of phenotypic severity for genetic and neurobiologic studies, and have potential utility for ascertaining incremental response to intervention.

Genetic linkage findings for DSM-IV nicotine withdrawal in two populations.

Nicotine withdrawal (NW) is both an important contributor to difficulty quitting cigarettes and because of mood-related withdrawal symptoms a problem of particular relevance to psychiatry. Twin-studies suggest that genetic factors influence NW (heritability = 45%). Only one previous linkage study has published findings on NW [Swan et al. (2006); Am J Med Genet Part B 141B:354-360; LOD = 2.7; Chr. 6 at 159 cM]. As part of an international consortium, genome-wide scans (using over 360 autosomal microsatellite markers) and telephone diagnostic interviews were conducted on 289 Australian (AUS) and 161 Finnish (FIN, combined (COMB) N = 450 families) families ascertained from twin registries through index-cases with a lifetime history of cigarette smoking. The statistical approach used an affected-sib-pair design (at least two adult full siblings reported a history of DSM-IV NW) and conducted the linkage analyses using MERLIN. Linkage signals with LOD scores >1.5 were found on two chromosomes: 6 (FIN: LOD = 1.93 at 75 cM) and 11 at two different locations (FIN: LOD = 3.55 at 17 cM, and AUS: LOD = 1.68 with a COMB: LOD = 2.30 at 123 cM). The multipoint LOD score of 3.55 on chromosome 11p15 in FIN met genomewide significance (P = 0.013 with 1,000 simulations). At least four strong candidate genes lie within or near this peak on chromosome 11: DRD4, TPH, TH, and CHRNA10. Other studies have reported that chromosome 11 may harbor genes associated with various aspects of smoking behavior. This study adds to that literature by highlighting evidence for NW.

Familial aggregation of quantitative autistic traits in multiplex versus simplex autism.

Recent research has suggested that the mode of inheritance for simplex autism (SA, one individual in the family affected) may be distinct from that for multiplex autism (MA, two or more individuals affected). Since sub clinical autistic traits have been observed in "unaffected" relatives of children with autism, we explored whether the distributions of such traits in families supported differential modes of genetic transmission for SA and MA autism. We measured patterns of familial aggregation of quantitative autistic traits (QAT) in children and parents in 80 SA families and 210 MA families, using the Social Responsiveness Scale. When considering all SA and MA siblings who scored below a uniform quantitative (clinical-level) severity threshold, MA brothers exhibited a distinct pathological shift in the distribution, compared to SA brothers (P < 0.0001). Such aggregation of QAT was also observed in fathers but not among females in MA families. Significant spousal correlations for QAT-suggestive of assortative mating-were observed in both SA and MA families, but neither group was characterized by a greater-than-chance level of concordant elevation among spousal pairs in this volunteer sample. Among male first degree relatives, there exist distinct patterns of QAT manifestation for simplex versus multiplex autism. These findings are consistent with the results of molecular genetic studies that have suggested differential modes of intergenerational transmission for SA and MA. Characterization of QAT and other endophenotypes among close relatives may be useful for reducing sample heterogeneity in future genetic and neurobiologic studies of autism.

Evidence for shared genetic influences on self-reported ADHD and autistic symptoms in young adult Australian twins.

Recent clinic-based and population-based studies have shown evidence of association between ADHD and autistic symptoms in children and adolescents as well as evidence for genetic overlap between these disorders. The objective of the current study was to confirm the association between autistic and ADHD symptoms in a young adult twin sample assessed by self-report, and investigate whether shared genetic and/or environmental factors can explain the association. We performed twin-based structural equation modeling using self-report data from 11 Social Responsiveness Scale (SRS) items and 12 DSM-IV ADHD inattentive and impulsive symptom items obtained from 674 young adult Australian twins. Phenotypic correlation between autistic and ADHD symptoms was moderate. The most parsimonious univariate models for SRS and ADHD included additive genetic effects and unique environmental effects, without sex differences. ADHD and autistic traits were both moderately heritable. In a bivariate model, genetic correlation (r(g)) between SRS and ADHD was 0.72. Our results suggest that in young adults, a substantial proportion of the genetic influences on self-reported autistic and ADHD symptoms may be shared between the two disorders.

Do attention deficit/hyperactivity disorder and oppositional defiant disorder influence preschool unintentional injury risk?

PURPOSE: This study explores the relationship among preschool attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), injury-risk-taking behavior, and unintentional injury. METHOD: An emergency department (ED) casecontrol study of parent-reported child behavior was conducted. FINDINGS: Children with ODD and ADHD had significantly more injury-risk-taking behaviors (odds ratio [OR] = 7.68, 95% confidence interval [CI] 2.25-26.25; OR = 4.87, 95% CI 1.17--20.28, respectively), and injured children had a 17-fold increase in high-risk-taking behaviors (OR 17.2, 95% CI 2.14--138.0). No significant association existed between ODD or ADHD and ED-treated unintentional injury. IMPLICATIONS: Disruptive behavior disorders are not major contributors to ED-treated unintentional injury in preschool children.

Autosomal linkage analysis for cannabis use behaviors in Australian adults.

Cannabis is the most commonly used illicit drug in developed and in developing nations. Twin studies have highlighted the role of genetic influences on early stages of cannabis use, such as a lifetime history of use, early-onset use and frequent use, however, we are not aware of any genomic studies that have examined these phenotypes. Using data on 2314 families consisting of 5600 adult Australian offspring and their parents, all of whom were scanned using 1399 unique autosomal markers, we conducted autosomal linkage analyses for lifetime history of cannabis initiation, early-onset cannabis use and frequency of use, using a variance components approach in the linkage package MERLIN. Suggestive evidence for linkage was found on chromosome 18 (LOD 2.14 for frequency of use, LOD 1.97 for initiation, at 90-97 cM) and also on chromosome 19 (LOD 1.92 for early-onset at 17 cM). These LOD scores did not meet genome-wide significance. Further replication of these linkage regions in other samples will be required, although these initial results suggest further targeted efforts on chromosome 18 may yield interesting candidate genes for early stages of cannabis-related behaviors.

An autosomal linkage scan for cannabis use disorders in the nicotine addiction genetics project.

CONTEXT: Despite accumulating evidence that there is a genetic basis for cannabis use disorders (ie, abuse and dependence), few studies have identified genomic regions that may harbor biological risk and protective factors. OBJECTIVE: To conduct autosomal linkage analyses that identify genomic regions that may harbor genes conferring a vulnerability to cannabis use disorders. DESIGN: In 289 Australian families who participated in the Nicotine Addiction Genetics Project, 423 autosomal markers were genotyped. Families were ascertained for heavy cigarette smoking. Linkage was conducted for DSM-IV cannabis dependence and for a novel factor score representing problems with cannabis use, including occurrence of 3 of 4 abuse criteria (excluding legal problems) and 6 DSM-IV dependence criteria. RESULTS: A maximum logarithm of odds (LOD) of 3.36 was noted for the cannabis problems factor score on chromosome arm 1p. An LOD of 2.2 was noted on chromosome 4 in the region of the gamma-aminobutyric acid type A gene cluster, including GABRA2, which has been implicated in drug use disorders. For DSM-IV cannabis dependence, a modest LOD score on chromosome 6 (1.42) near cannabinoid receptor 1 (CNR1) was identified. In addition, support for an elevation on chromosome 3, identified in prior independent studies, was noted for the factor score and cannabis dependence (LOD, 1.4). CONCLUSIONS: Genes such as ELTD1 on chromosome 1, in addition to genes on chromosomes 4 (eg, GABRA2) and 6 (eg, CNR1), may be associated with the genetic risk for cannabis use disorders. We introduce a novel quantitative phenotype, a cannabis problems factor score composed of DSM-IV abuse and dependence criteria, that may be useful for future linkage and association studies.

Poor utility of the age of onset criterion for DSM-IV attention deficit/hyperactivity disorder: recommendations for DSM-V and ICD-11.

BACKGROUND: To test whether the retrospective reporting of the age of onset impairment criterion for attention deficit/hyperactivity disorder (ADHD) required in the Diagnostic and Statistical Manual of Mental Disorders - IV (DSM-IV) complicates identification of new and known child and adolescent cases later in life. METHODS: A birth-records-based cohort of twins assessed at ages 7 to 19 years were blindly reassessed five years later using the MAGIC interview. Study outcome measures were differences in reported ages of onset for attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD) and major depressive disorder (MDD). RESULTS: For all age groups and respondents (parent on youth or youth self-report), later ages of ADHD onset were reported five years later. The same phenomenon was also present for the other diagnostic groups. Of the initial ADHD individuals who continued to meet all other ADHD criteria at follow-up, 46% failed the age of onset criterion five years later. When ignoring the age of onset criterion, late onsets of ages 7-16 years accounted for about 10% of all ADHD. CONCLUSIONS: Use of the DSM-IV age of onset criterion for attention deficit/hyperactivity disorder in the assessment of adolescents and young adults results in under-identification of affected individuals. Consideration should be given to revising the current nomenclatures to reflect the reality of retrospective reporting errors in age of onset as well as the presence of late onset cases.

Addictions biology: haplotype-based analysis for 130 candidate genes on a single array.

AIMS: To develop a panel of markers able to extract full haplotype information for candidate genes in alcoholism, other addictions and disorders of mood and anxiety. METHODS: A total of 130 genes were haplotype tagged and genotyped in 7 case/control populations and 51 reference populations using Illumina GoldenGate SNP genotyping technology, determining haplotype coverage. We also constructed and determined the efficacy of a panel of 186 ancestry informative markers. RESULTS: An average of 1465 loci were genotyped at an average completion rate of 91.3%, with an average call rate of 98.3% and replication rate of 99.7%. Completion and call rates were lowered by the performance of two datasets, highlighting the importance of the DNA quality in high throughput assays. A comparison of haplotypes captured by the Addictions Array tagging SNPs and commercially available whole-genome arrays from Illumina and Affymetrix shows comparable performance of the tag SNPs to the best whole-genome array in all populations for which data are available. CONCLUSIONS: Arrays of haplotype-tagged candidate genes, such as this addictions-focused array, represent a cost-effective approach to generate high-quality SNP genotyping data useful for the haplotype-based analysis of panels of genes such as these 130 genes of interest to alcohol and addictions researchers. The inclusion of the 186 ancestry informative markers allows for the detection and correction for admixture and further enhances the utility of the array.