Gray matter volume associations in youth with ADHD features of inattention and hyperactivity/impulsivity.

BACKGROUND: Prior research has shown smaller cortical and subcortical gray matter volumes among individuals with attention-deficit/hyperactivity disorder (ADHD). However, neuroimaging studies often do not differentiate between inattention and hyperactivity/impulsivity, which are distinct core features of ADHD. The present study uses an approach to disentangle overlapping variance to examine the neurostructural heterogeneity of inattention and hyperactivity/impulsivity dimensions. METHODS: We analyzed data from 10,692 9- to 10-year-old children from the Adolescent Brain Cognitive Development (ABCD) Study. Confirmatory factor analysis was used to derive factors representing inattentive and hyperactive/impulsive traits. We employed structural equation modeling to examine these factors' associations with gray matter volume while controlling for the shared variance between factors. RESULTS: Greater endorsement of inattentive traits was associated with smaller bilateral caudal anterior cingulate and left parahippocampal volumes. Greater endorsement of hyperactivity/impulsivity traits was associated with smaller bilateral caudate and left parahippocampal volumes. The results were similar when accounting for socioeconomic status, medication, and in-scanner motion. The magnitude of these findings increased when accounting for overall volume and intracranial volume, supporting a focal effect in our results. CONCLUSIONS: Inattentive and hyperactivity/impulsivity traits show common volume deficits in regions associated with visuospatial processing and memory while at the same time showing dissociable differences, with inattention showing differences in areas associated with attention and emotion regulation and hyperactivity/impulsivity associated with volume differences in motor activity regions. Uncovering such biological underpinnings within the broader disorder of ADHD allows us to refine our understanding of ADHD presentations.

Mapping potential pathways from polygenic liability through brain structure to psychological problems across the transition to adolescence.

BACKGROUND: We used a polygenic score for externalizing behavior (extPGS) and structural MRI to examine potential pathways from genetic liability to conduct problems via the brain across the adolescent transition. METHODS: Three annual assessments of child conduct problems, attention-deficit/hyperactivity problems, and internalizing problems were conducted across across 9-13 years of age among 4,475 children of European ancestry in the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®). RESULTS: The extPGS predicted conduct problems in each wave (R2 = 2.0%-2.9%). Bifactor models revealed that the extPRS predicted variance specific to conduct problems (R2 = 1.7%-2.1%), but also variance that conduct problems shared with other measured problems (R2 = .8%-1.4%). Longitudinally, extPGS predicted levels of specific conduct problems (R2 = 2.0%), but not their slope of change across age. The extPGS was associated with total gray matter volume (TGMV; R2 = .4%) and lower TGMV predicted both specific conduct problems (R2 = 1.7%-2.1%) and the variance common to all problems in each wave (R2 = 1.6%-3.1%). A modest proportion of the polygenic liability specific to conduct problems in each wave was statistically mediated by TGMV. CONCLUSIONS: Across the adolescent transition, the extPGS predicted both variance specific to conduct problems and variance shared by all measured problems. The extPGS also was associated with TGMV, which robustly predicted conduct problems. Statistical mediation analyses suggested the hypothesis that polygenic variation influences individual differences in brain development that are related to the likelihood of conduct problems during the adolescent transition, justifying new research to test this causal hypothesis.

Multivariate analytical approaches for investigating brain-behavior relationships.

Background: Many studies of brain-behavior relationships rely on univariate approaches where each variable of interest is tested independently, which does not allow for the simultaneous investigation of multiple correlated variables. Alternatively, multivariate approaches allow for examining relationships between psychopathology and neural substrates simultaneously. There are multiple multivariate methods to choose from that each have assumptions which can affect the results; however, many studies employ one method without a clear justification for its selection. Additionally, there are few studies illustrating how differences between methods manifest in examining brain-behavior relationships. The purpose of this study was to exemplify how the choice of multivariate approach can change brain-behavior interpretations. Method: We used data from 9,027 9- to 10-year-old children from the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) to examine brain-behavior relationships with three commonly used multivariate approaches: canonical correlation analysis (CCA), partial least squares correlation (PLSC), and partial least squares regression (PLSR). We examined the associations between psychopathology dimensions including general psychopathology, attention-deficit/hyperactivity symptoms, conduct problems, and internalizing symptoms with regional brain volumes. Results: The results of CCA, PLSC, and PLSR showed both consistencies and differences in the relationship between psychopathology symptoms and brain structure. The leading significant component yielded by each method demonstrated similar patterns of associations between regional brain volumes and psychopathology symptoms. However, the additional significant components yielded by each method demonstrated differential brain-behavior patterns that were not consistent across methods. Conclusion: Here we show that CCA, PLSC, and PLSR yield slightly different interpretations regarding the relationship between child psychopathology and brain volume. In demonstrating the divergence between these approaches, we exemplify the importance of carefully considering the method's underlying assumptions when choosing a multivariate approach to delineate brain-behavior relationships.

Atypical Functional Network Properties and Associated Dimensions of Child Psychopathology During Rest and Task Performance.

Background: When brain networks deviate from typical development, this is thought to contribute to varying forms of psychopathology. However, research has been limited by the reliance on discrete diagnostic categories that overlook the potential for psychological comorbidity and the dimensional nature of symptoms. Methods: This study examined the topology of functional networks in association with 4 bifactor-defined psychopathology dimensions-general psychopathology, internalizing symptoms, conduct problems, and attention-deficit/hyperactivity disorder symptoms-via the Child Behavior Checklist in a sample of 3568 children from the ABCD (Adolescent Brain Cognitive Development) Study. Local and global graph theory metrics were calculated at rest and during tasks of reward processing, inhibition, and working memory. Results: Greater attention-deficit/hyperactivity disorder symptoms were associated with reduced modularity across rest and tasks as well as reduced local efficiency in motor networks at rest. Results survived sensitivity analyses for medication and socioeconomic status. Greater conduct problem symptoms were associated with reduced modularity on working memory and reward processing tasks; however, these results did not persist after sensitivity analyses. General psychopathology and internalizing symptoms showed no significant network associations. Conclusions: Our findings suggest reduced efficiency in topology in those with greater attention-deficit/hyperactivity disorder symptoms across 4 critical cognitive states, with conduct problems also showing network deficits, although less consistently. This may suggest that modularity deficits are a neurobiological marker of externalizing behavior in children. Such specificity has not been demonstrated before using graph theory metrics and has the potential to redefine our understanding of network deficits in children with psychopathology symptoms.

General and Specific Factors of Environmental Stress and Their Associations With Brain Structure and Dimensions of Psychopathology.

Background: Early-life stressors can adversely affect the developing brain. While hierarchical modeling has established the existence of a general factor of psychopathology, no studies have modeled a general factor of environmental stress and related this factor to brain development. Using a large sample of children from the ABCD (Adolescent Brain Cognitive Development) Study, the current study aimed to identify general and specific factors of environmental stress and test their associations with brain structure and psychopathology. Methods: In a sample of 11,878 children, bifactor modeling and higher-order (second-order) modeling identified general and specific factors of environmental stress: family dynamics, interpersonal support, neighborhood socioeconomic status deprivation, and urbanicity. Structural equation modeling was performed to examine associations between these factors and regional gray matter volume (GMV) and cortical thickness as well as general and specific factors of psychopathology. Results: The general environmental stress factor was associated with globally smaller cortical and subcortical GMV as well as thinner cortices across widespread regions. Family dynamics and neighborhood socioeconomic status deprivation were associated with smaller GMV in focal regions. Urbanicity was associated with larger cortical and subcortical GMV and thicker cortices in frontotemporal regions. The environmental factors were associated with psychopathology in the expected directions. The general factors of environmental stress and psychopathology were both predictors of smaller GMV in children, while remaining distinct from each other. Conclusions: This study reveals a unifying model of environmental influences that illustrates the inherent organization of environmental stressors and their relationship to brain structure and psychopathology.

The association between latent trauma and brain structure in children.

The developing brain is marked by high plasticity, which can lead to vulnerability to early life stressors. Previous studies indicate that childhood maltreatment is associated with structural aberrations across a number of brain regions. However, prior work is limited by small sample sizes, heterogeneous age groups, the examination of one structure in isolation, the confounding of different types of early life stressors, and not accounting for socioeconomic status. These limitations may contribute to high variability across studies. The present study aimed to investigate how trauma is specifically associated with cortical thickness and gray matter volume (GMV) differences by leveraging a large sample of children (N = 9270) from the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®). A latent measure of trauma exposure was derived from DSM-5 traumatic events, and we related this measure of trauma to the brain using structural equation modeling. Trauma exposure was associated with thinner cortices in the bilateral superior frontal gyri and right caudal middle frontal gyrus (pfdr-values < .001) as well as thicker cortices in the left isthmus cingulate and posterior cingulate (pfdr-values ≤ .027), after controlling age, sex, and race/ethnicity. Furthermore, trauma exposure was associated with smaller GMV in the right amygdala and right putamen (pfdr-values ≤ .048). Sensitivity analyses that controlled for income and parental education were largely consistent with the main findings for cortical thickness. These results suggest that trauma may be an important risk factor for structural aberrations, specifically for cortical thickness differences in frontal and cingulate regions in children.

Association of gray matter volumes with general and specific dimensions of psychopathology in children.

Childhood is an important time for the manifestation of psychopathology. Psychopathology is characterized by considerable comorbidity which is mirrored in the underlying neural correlates of psychopathology. Both common and dissociable variations in brain volume have been found across multiple mental disorders in adult and youth samples. However, the majority of these studies used samples with broad age ranges which may obscure developmental differences. The current study examines associations between regional gray matter volumes (GMV) and psychopathology in a large sample of children with a narrowly defined age range. We used data from 9607 children 9-10 years of age collected as part of the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®). A bifactor model identified a general psychopathology factor that reflects common variance across disorders and specific factors representing internalizing symptoms, ADHD symptoms, and conduct problems. Brain volume was acquired using 3T MRI. After correction for multiple testing, structural equation modeling revealed nearly global inverse associations between regional GMVs and general psychopathology and conduct problems, with associations also found for ADHD symptoms (pfdr-values ≤ 0.048). Age, sex, and race were included as covariates. Sensitivity analyses including total GMV or intracranial volume (ICV) as covariates support this global association, as a large majority of region-specific results became nonsignificant. Sensitivity analyses including income, parental education, and medication use as additional covariates demonstrate largely convergent results. These findings suggest that globally smaller GMVs are a nonspecific risk factor for general psychopathology, and possibly for conduct problems and ADHD as well.

Correction to Moore et al. (2020).

Reports an error in "Criterion validity and relationships between alternative hierarchical dimensional models of general and specific psychopathology" by Tyler M. Moore, Antonia N. Kaczkurkin, E. Leighton Durham, Hee Jung Jeong, Malerie G. McDowell, Randolph M. Dupont, Brooks Applegate, Jennifer L. Tackett, Carlos Cardenas-Iniguez, Omid Kardan, Gaby N. Akcelik, Andrew J. Stier, Monica D. Rosenberg, Donald Hedeker, Marc G. Berman and Benjamin B. Lahey (Journal of Abnormal Psychology, Advanced Online Publication, Jul 16, 2020, np). In the article (http://dx.doi.org/10.1037/abn0000601), an acknowledgment is missing from the author note. The missing acknowledgement is included in the erratum. (The following abstract of the original article appeared in record 2020-50590-001.) Psychopathology can be viewed as a hierarchy of correlated dimensions. Many studies have supported this conceptualization, but they have used alternative statistical models with differing interpretations. In bifactor models, every symptom loads on both the general factor and 1 specific factor (e.g., internalizing), which partitions the total explained variance in each symptom between these orthogonal factors. In second-order models, symptoms load on one of several correlated lower-order factors. These lower-order factors load on a second-order general factor, which is defined by the variance shared by the lower-order factors. Thus, the factors in second-order models are not orthogonal. Choosing between these valid statistical models depends on the hypothesis being tested. Because bifactor models define orthogonal phenotypes with distinct sources of variance, they are optimal for studies of shared and unique associations of the dimensions of psychopathology with external variables putatively relevant to etiology and mechanisms. Concerns have been raised, however, about the reliability of the orthogonal specific factors in bifactor models. We evaluated this concern using parent symptom ratings of 9-10 year olds in the ABCD Study. Psychometric indices indicated that all factors in both bifactor and second-order models exhibited at least adequate construct reliability and estimated replicability. The factors defined in bifactor and second-order models were highly to moderately correlated across models, but have different interpretations. All factors in both models demonstrated significant associations with external criterion variables of theoretical and clinical importance, but the interpretation of such associations in second-order models was ambiguous due to shared variance among factors. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Criterion validity and relationships between alternative hierarchical dimensional models of general and specific psychopathology.

[Correction Notice: An Erratum for this article was reported in Vol 129(7) of Journal of Abnormal Psychology (see record 2020-72912-001). In the article (http://dx.doi.org/10.1037/abn0000601), an acknowledgment is missing from the author note. The missing acknowledgement is included in the erratum.] Psychopathology can be viewed as a hierarchy of correlated dimensions. Many studies have supported this conceptualization, but they have used alternative statistical models with differing interpretations. In bifactor models, every symptom loads on both the general factor and 1 specific factor (e.g., internalizing), which partitions the total explained variance in each symptom between these orthogonal factors. In second-order models, symptoms load on one of several correlated lower-order factors. These lower-order factors load on a second-order general factor, which is defined by the variance shared by the lower-order factors. Thus, the factors in second-order models are not orthogonal. Choosing between these valid statistical models depends on the hypothesis being tested. Because bifactor models define orthogonal phenotypes with distinct sources of variance, they are optimal for studies of shared and unique associations of the dimensions of psychopathology with external variables putatively relevant to etiology and mechanisms. Concerns have been raised, however, about the reliability of the orthogonal specific factors in bifactor models. We evaluated this concern using parent symptom ratings of 9-10 year olds in the ABCD Study. Psychometric indices indicated that all factors in both bifactor and second-order models exhibited at least adequate construct reliability and estimated replicability. The factors defined in bifactor and second-order models were highly to moderately correlated across models, but have different interpretations. All factors in both models demonstrated significant associations with external criterion variables of theoretical and clinical importance, but the interpretation of such associations in second-order models was ambiguous due to shared variance among factors. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Age Differences in Expression of Generalized and Social Anxiety Among Youth with Autism Spectrum Disorder.

This study examined differences in generalized and social anxiety symptoms across two age groups of children with autism spectrum disorder (ASD) while accounting for overall anxiety level, gender, and intellectual functioning. Older children (12-18 years) expressed more overall and social anxiety symptoms than younger children (6-11 years), and social anxiety symptoms were predominant in the older group. Younger children expressed more generalized anxiety symptoms than the older youth, and there was a trend for generalized anxiety symptoms to be more dominant in the younger group. Findings are consistent with theory of differential expression of specific anxiety symptoms across different ages seen with typically developing children, yet social evaluative concerns may be even stronger for adolescents with ASD.

Significant association of ANKK1 and detection of a functional polymorphism with nicotine dependence in an African-American sample.

The dopaminergic system in the brain plays a critical role in nicotine addiction. Genetic variants in the dopaminergic system, including those in dopamine receptor genes, represent plausible candidates for the genetic study of nicotine dependence (ND). We investigated various polymorphisms in the dopamine D(2) receptor gene (DRD2) and its neighboring ankyrin repeats and kinase domain containing 1 gene (ANKK1) to determine whether they were associated with ND. We examined 16 single nucleotide polymorphisms (SNPs) at DRD2 and 7 SNPs at ANKK1 in our Mid-South Tobacco Family cohort, which consisted of 2037 participants representing two distinct American populations. Several SNPs (rs7131056, rs4274224, rs4648318, and rs6278) in DRD2, along with the Taq IA polymorphism (rs1800497) in ANKK1, revealed initial significant associations with ND in European Americans, but not after correction for multiple testing, indicating a weak association of DRD2 with ND. In contrast, associations for ANKK1 with ND in the African-American and pooled samples, specifically for SNP rs2734849, remained significant after correction. With a non-synonymous G to A transition, rs2734849 produces an amino-acid change (arginine to histidine) in C-terminal ankyrin repeat domain of ANKK1. Using the luciferase reporter assay, we further demonstrated that the variant alters expression level of NF-kappaB-regulated genes. Since DRD2 expression is regulated by transcription factor NF-kappaB, we suspect that rs2734849 may indirectly affect dopamine D(2) receptor density. We conclude that ANKK1 is associated with ND and polymorphism rs2734849 in ANKK1 represents a functional causative variant for ND in African-American smokers.

Significant association of DRD1 with nicotine dependence.

Epidemiologic studies have strongly implicated genetics in smoking behavior. Genes in the dopaminergic system, which mediates the reinforcing and dependence-producing properties of nicotine, are plausible candidates for roles in nicotine dependence (ND). In this study, we examined five single-nucleotide polymorphisms (SNPs) within or near the dopamine D(1) receptor gene (DRD1) for their association with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). The samples were obtained from 2,037 participants representing 200 European American (EA) and 402 African American (AA) families. Although we found significant associations of SNPs rs265973, rs686, and rs4532 in the AA sample; of rs4532 in the EA sample; and of rs265975, rs686, and rs4532 in the pooled sample with various ND measures, only the association of rs686 in the AA sample and of rs686 and rs4532 in the pooled sample remained significant after correction for multiple testing. Haplotype-based association analysis revealed that haplotype C-T-A, formed by rs265973, rs265975, and rs686, was significantly associated with all three ND measures in both the AA and the pooled sample. Another haplotype, T-A-T, formed by rs265975, rs686, and rs4532, showed a significant association with FTND in the pooled sample. Furthermore, in a luciferase reporter assay, rs686, located in the 3' untranslated region, caused differential luciferase activities, indicating that rs686 is a functional polymorphism affecting expression of DRD1.

Association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene (NTRK2) with vulnerability to nicotine dependence in African-Americans and European-Americans.

BACKGROUND: The gene encoding neurotrophic tyrosine kinase receptor 2 (NTRK2) has been localized to a region on chromosome 9q22-q23 that showed a "suggestive" linkage to nicotine dependence (ND) in our previous linkage analyses. However, no association of NTRK2 with ND has been identified. METHODS: Family-based association analyses of 2037 participants (1366 African Americans [AA], 671 European Americans [EA]) representing 602 nuclear families were performed to evaluate association of nine single nucleotide polymorphisms (SNPs) within NTRK2 with ND. RESULTS: Individual SNP-based association analysis indicated that in the EA sample, SNPs rs1659400 and rs1187272 were significantly associated with at least one adjusted ND measure. Haplotype analysis revealed that even after Bonferroni correction, the haplotype T-T-A of rs1659400-rs1187272-rs1122530 had a highly significant positive association, with adjusted ND measures in the EA sample (max Z = 3.78; p = .0001, frequency 59.9%). We further identified a major haplotype, T-G-C-A-A (26%), formed by rs993315-rs736744-rs920776-rs4075274-rs729560, which showed a significant positive association (max Z = 2.97, p = .003) with adjusted ND measures in the AA sample. CONCLUSIONS: These results strongly suggest that NTRK2 is a susceptibility gene for ND. These findings imply that NTRK2 plays a role in the etiology of ND and represents an important biological candidate for further investigation.

A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans.

Epidemiological studies have demonstrated that genetic factors account for at least 50% of the liability for nicotine dependence (ND). Although several linkage studies have been conducted, all samples to date were primarily of European origin. In this study, we conducted a genomewide scan of 1,261 individuals, representing 402 nuclear families, of African American (AA) origin. We examined 385 autosomal microsatellite markers for ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). After performing linkage analyses using various methods implemented in the GENEHUNTER and S.A.G.E. programs, we found a region near marker D10S1432 on chromosome 10q22 that showed a significant linkage to indexed SQ, with a maximum LOD score of 4.17 at 92 cM and suggestive linkage to HSI, SQ, and log-transformed SQ. Additionally, we identified three regions that met the criteria for suggestive linkage to at least one ND measure: on chromosomes 9q31 at marker D9S1825, 11p11 between markers D11S1993 and D11S1344, and 13q13 between markers D13S325 and D13S788. Other locations on chromosomes 15p11, 17q25, and 18q12 exhibited some evidence of linkage for ND (LOD >1.44). The four regions with significant or suggestive linkage were positive for multiple ND measures by multiple statistical methods. Some of these regions have been linked to smoking behavior at nominally significant levels in other studies, which provides independent replication of the regions for ND in different cohorts. In summary, we found significant linkage on chromosome 10q22 and suggestive linkage on chromosomes 9, 11, and 13 for major genetic determinants of ND in an AA sample. Further analysis of these positive regions by fine mapping and/or association analysis is thus warranted. To our knowledge, this study represents the first genomewide linkage scan of ND in an AA sample.

Significant association of BDNF haplotypes in European-American male smokers but not in European-American female or African-American smokers.

Brain-derived neurotrophic factor (BDNF) influences dopamine and serotonin neurotransmission in the brain, both of which are involved in the reward system of addiction. The BDNF gene is located in a genomic region on chromosome 11p where we and others have found 'significant' linkage to nicotine dependence (ND). We tested the potential role of variants within BDNF in vulnerability to ND, which was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). Six single nucleotide polymorphisms (SNPs) in BDNF were analyzed in an extensively phenotyped cohort of 602 nuclear families with smokers and non-smokers of African-American (AA) or European-American (EA) ancestry. Individual SNP analysis revealed that two SNPs in the pooled male and three SNPs in the EA male samples were significantly associated with at least one adjusted ND measure. However, none of these associations remained significant after correction for multiple testing. Haplotype analysis of rs6484320-rs988748-rs2030324-rs7934165 revealed that a major T-C-T-G haplotype was significantly associated, even after Bonferroni correction, with the three ND measures in the pooled and EA male samples (maximum Z = 3.00, P = 0.002 and maximum Z = 3.13, P = 0.0009 for SQ, respectively). No significant association of a major haplotype with ND was found in the AA or EA female smokers. The significant association of BDNF variants with ND implies that this gene plays a role in the etiology of ND in EAs and that its involvement is gender specific. BDNF may warrant further investigation in ND.

Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence.

DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within the 7p11 region that showed a 'suggestive linkage' to ND in our previous genome-wide scan in the Framingham Heart Study population. In the present study, we tested eight single nucleotide polymorphisms (SNPs) within DDC for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) score, in a total of 2037 smokers and non-smokers from 602 nuclear families of African- or European-American (AA or EA, respectively) ancestry. Association analysis for individual SNPs using the PBAT-GEE program indicated that SNP rs921451 was significantly associated with two of the three adjusted ND measures in the EA sample (P=0.01-0.04). Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in the AA sample, which was significantly associated with all three adjusted ND measures after correction for multiple testing (min Z=-2.78, P=0.006 for HSI). In contrast, we found a high-risk T-G-T-G haplotype for a different SNP combination in the EA sample, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association after Bonferroni correction with the SQ and FTND score (max Z=2.73, P=0.005 for FTND). In summary, our findings provide the first evidence for the involvement of DDC in the susceptibility to ND and, further, reveal the racial specificity of its impact.

Single- and multilocus allelic variants within the GABA(B) receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence.

Twelve single-nucleotide polymorphisms (SNPs) in the human gamma-aminobutyric acid type B (GABA(B)) receptor subunit 2 gene (GABAB2) were tested for association with nicotine dependence (ND) in an extensively phenotyped cohort of 1,276 smokers and nonsmokers, representing approximately 404 nuclear families of African American (AA) or European American (EA) origin. The GABAB2 gene encodes a subunit of the GABA(B) receptor for GABA, an inhibitory neurotransmitter involved in the regulation of many physiological and psychological processes in the brain. The gene is located within a region of chromosome 9q22 that showed a "suggestive" linkage to ND. Individual SNP analysis performed using the PBAT-GEE program indicated that two SNPs in the AAs and four SNPs in the EAs were significantly associated with ND. Haplotype analysis using the Family-Based Association Test revealed that, even after Bonferroni correction, the haplotype C-C-G of rs2491397-rs2184026-rs3750344 had a significant positive association with ND in both the pooled and the AA samples. In the EAs, we identified two haplotypes, C-A-C-A and T-A-T-A, formed by SNPs rs1435252-rs378042-rs2779562-rs3750344, that showed a highly significant negative and positive association with ND, respectively. In summary, our findings provide evidence of a significant association of GABAB2 variants with ND, implying that this gene plays an important role in the etiology of this drug addiction.

A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population.

BACKGROUND: Although many years of genetic epidemiological studies have demonstrated that genetics plays a significant role in determining smoking behavior, little information is available on genomic loci or genes affecting nicotine dependence. Several susceptibility chromosomal regions for nicotine dependence have been reported, but few have received independent confirmation. To identify susceptibility loci for nicotine dependence, 313 extended pedigrees selected from the Framingham Heart Study population were analyzed by both the GENEHUNTER and S.A.G.E. programs. RESULTS: After performing linkage analyses on the 313 extended Framingham Heart Study families, the EM Haseman-Elston method implemented in GENEHUNTER provided evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 9, 14, and 17. Multipoint sib-pair regression analysis using the SIBPAL program of S.A.G.E. on 1389 sib pairs that were split from the 313 extended families identified suggestive linkage of smoking rate to chromosomes 4, 7, and 17. Of these identified positive regions for nicotine dependence, loci on chromosomes 7, 11, and 17 were identified by both GENEHUNTER and S.A.G.E. programs. CONCLUSION: Our genome-wide scan results on the Framingham Heart Study data provide evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 4, 7, 9, 14, and 17. These findings suggest that some of these regions may harbor susceptibility loci for nicotine dependence, and warrant further investigation in this and other populations.

Mapping susceptibility loci for alcohol consumption using number of grams of alcohol consumed per day as a phenotype measure.

BACKGROUND: There is substantial evidence for a significant genetic component to the risk for alcoholism. However, susceptibility loci or genes for alcohol dependence remain largely unknown. To identify susceptibility loci for alcohol dependence, we selected 329 extended families from the Framingham Heart Study population in which at least one family member reported alcohol consumption during the interview in 1970-1971, and performed genome-wide linkage analyses using various analytical methods. RESULTS: Multi-point sib-pair regression analysis using the SIBPAL program of S.A.G.E. provided strong evidence for linkage of alcohol dependence to chromosomes 9 (p-value < 0.0001) and weak evidence to chromosomes 15 and 16 (p-value < 0.005). To confirm these findings, we re-analyzed the same data set by various methods implemented in GENEHUNTER and found that only one region was significant with a LOD score > 2.0 by the variance-component method. This region is located on chromosome 9 between markers GATA21F05 and GATA81C04. CONCLUSION: Analyses of the Framingham Heart Study population provided evidence of genetic susceptibility loci for alcohol dependence on chromosomes 9, 15, and 16. The genomic region identified on chromosome 9 was particularly interesting because the region has also been previously reported to be linked to alcohol dependence in the American Indian population by another group.

The relation of defensive style and thematic content to children's enjoyment and comprehension of joking riddles.

Joking riddles of low, moderate, and high aggressive content were administered to 60 normal elementary school boys of average intelligence, categorized into three groups of 20 based on their characteristic defensive styles (constricted, flexible, and impulsive) of dealing with aggressive impulses. Both moderately and highly aggressive riddles were enjoyed more. Though no main effect for defensive style was found for either riddle enjoyment or comprehension, complex interactions among defensive style, level of aggression, and time of presentation emerged as significant.