Rosalind J. Neuman

A genome-wide association study of alcohol dependence

Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10−5, but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor α2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.

Determining zygosity in the Vietnam Era Twin Registry: an approach using questionnaires

The Vietnam Era Twin Registry (VETR) is a registry of 7375 American male veteran twin pairs born between 1939 and 1955 who served in the armed forces of the United States between 1964 and 1975. Optimal use of registry data requires the determination of zygosity. Two approaches are available: analysis of blood genetic marker systems and responses of twins to questions about sibling similarity. Zygosity for the VETR was determined using the questionnaire technique supplemented with blood group typing data abstracted from military records. After comparing four alternative zygosity assignment methods, a logistic regression technique which uses discriminating variables based on race was selected. The approach is similar to that described by Magnus et al. (1983) in their study of Norwegian twins, suggesting that questionnaire responses are independent of nationality and reinforcing the reliability of the questionnaire method for zygosity ascertainment.

Brain-Derived Neurotrophic Factor and Autoantibodies to Neural Antigens in Sera of Children with Autistic Spectrum Disorders, Landau-Kleffner Syndrome, and Epilepsy

BACKGROUND Brain derived neurotrophic factor (BDNF) elevation in newborn sera predicts intellectual/social developmental abnormalities. Other autoantibodies (AAs) to endothelial cells (ECs) and myelin basic protein (MBP) are also elevated in some children. We tested relationships between BDNF, BDNF AAs, and other AAs in children with these disorders. METHODS BDNF levels and IgG/IgM autoantibodies to BDNF, ECs, MBP, and histones were measured in children with autism, childhood disintegrative disorder (CDD), pervasive developmental delay-not otherwise specified (PDD-nos), acquired epilepsy, Landau-Kleffner syndrome (LKS); healthy children (HC), and children with non-neurological illnesses (NNI). RESULTS Mean BDNF levels were elevated in children with autism and CDD, (p < or = 0.0002) compared to HC or NNI. Mean IgG and IgM BDNF AAs were elevated in children with autism, CDD and epilepsy (p < or = 0.0005) compared to HC but not to NNI. Mean IgM AA EC titers detected by immunocytochemistry were higher in autism, PDD-NOS, epilepsy, and LKS (p < or = 0.005) compared to HC and NNI. While mean ELISA IgG EC AAs were higher in autism and PPD-NOS (p < 0.005) compared to HC but not NNI, ELISA IgM EC AAs were higher in children with autism, CDD, PDD-NOS, and epilepsy compared to both HC and NNI (p < 0.0005). Mean anti-MBP IgG and IgM titers were higher in all study groups (p < 0.005) except for LKS compared to both HC and NNI. CONCLUSION Children with developmental disorders and epilepsy have higher AAs to several neural antigens compared to controls. The presence of both BDNF AAs and elevated BDNF levels in some children with autism and CDD suggests a previously unrecognized interaction between the immune system and BDNF.

Prenatal Smoking Exposure and Dopaminergic Genotypes Interact to Cause a Severe ADHD Subtype

BACKGROUND In utero exposure to smoking and alcohol are common risk factors that have been associated with attention-deficit/hyperactivity disorder (ADHD) in human beings and animal models. Furthermore, molecular studies have focused on the association between ADHD and DNA polymorphisms in dopamine pathway-related genes. We examined the joint effects of genetic and prenatal substance exposures on DSM-IV and population-defined subtypes of ADHD. METHODS Logistic regression was used to assess the relationship between ADHD subtypes, DAT1 and DRD4 polymorphisms, and prenatal substance exposures in a birth-record sample of male and female twin pairs, aged 7-19 years. RESULTS Interactions between prenatal exposure to smoking and variations in the DAT1 and DRD4 loci were observed in children with either the DSM-IV or population-defined ADHD combined subtypes. The odds of a diagnosis of DSM-IV combined subtype was 2.9 times greater in twins who had inherited the DAT1 440 allele and who were exposed, than in unexposed twins without the risk allele. The OR was 2.6 in the population-defined subtype. Odds ratios for the DRD4 seven-repeat allele were 3.0 (2.8) in the population-defined (DSM-IV) combined ADHD subtypes. The OR for exposed children with both alleles was 9.0 (95% confidence interval=2.0-41.5) for the population-defined combined subtypes. CONCLUSIONS Results indicate that smoking during pregnancy is associated with specific subtypes of ADHD in genetically susceptible children.

Genetic Studies of Affective Disorders: Should We Be Starting with Childhood Onset Probands?

OBJECTIVE The objective of this study is to test whether the presence of childhood onset affective disorder identifies families with increased incidence and severity of affective disorders. METHOD Family history information was collected on the first and second degree relatives and first cousins age > or = 15 years of 22 children with bipolar affective disorder, 54 children with major depressive disorder, and 31 psychiatrically normal children. RESULTS Compared with the relatives of normal children, relatives identified through children with bipolar affective disorder or major depressive disorder had elevated rates of affective disorders and increased severity of affective disorders as judged by earlier age of onset and increased suicide attempts. Segregation analyses could reject purely environmental transmission of illness. CONCLUSION Ascertaining families through childhood onset affective disorder probands identifies extended pedigrees with high incidence and severity of affective disorders. These families may be more appropriate for genetic analyses than are families of adult probands.

Variants in the CD36 gene associate with the metabolic syndrome and high-density lipoprotein cholesterol

A region along chromosome 7q was recently linked to components of the metabolic syndrome (MetS) in several genome-wide linkage studies. Within this region, the CD36 gene, which encodes a membrane receptor for long-chain fatty acids and lipoproteins, is a potentially important candidate. CD36 has been documented to play an important role in fatty acid metabolism in vivo and subsequently may be involved in the etiology of the MetS. The protein also impacts survival to malaria and the influence of natural selection has resulted in high CD36 genetic variability in populations of African descent. We evaluated 36 tag SNPs across CD36 in the HyperGen population sample of 2020 African-Americans for impact on the MetS and its quantitative traits. Five SNPs associated with increased odds for the MetS [P = 0.0027-0.03, odds ratio (OR) = 1.3-1.4]. Coding SNP, rs3211938, previously shown to influence malaria susceptibility, is documented to result in CD36 deficiency in a homozygous subject. This SNP conferred protection against the MetS (P = 0.0012, OR = 0.61, 95%CI: 0.46-0.82), increased high-density lipoprotein cholesterol, HDL-C (P = 0.00018) and decreased triglycerides (P = 0.0059). Fifteen additional SNPs associated with HDL-C (P = 0.0028-0.044). We conclude that CD36 variants may impact MetS pathophysiology and HDL metabolism, both predictors of the risk of heart disease and type 2 diabetes.

A Risk Allele for Nicotine Dependence in CHRNA5 Is a Protective Allele for Cocaine Dependence

BACKGROUND A nonsynonymous coding polymorphism, rs16969968, of the CHRNA5 gene that encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence. The goal of this study was to examine the association of this variant with cocaine dependence. METHODS Genetic association analysis was performed in two independent samples of unrelated case and control subjects: 1) 504 European Americans participating in the Family Study on Cocaine Dependence (FSCD) and 2) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholism (COGA). RESULTS In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (odds ratio = .67 per allele, p = .0045, assuming an additive genetic model), but in the reverse direction compared with that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD. CONCLUSIONS The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways.

Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with ‘pleasurable buzz’ during early experimentation with smoking

Aims To extend the previously identified association between a single nucleotide polymorphism (SNP) in neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) and nicotine dependence to current smoking and initial smoking-experience phenotypes. Design, setting, participants Case–control association study with a community-based sample, comprising 363 Caucasians and 72 African Americans (203 cases, 232 controls). Measurements Cases had smoked ≥ five cigarettes/day for ≥ 5 years and had smoked at their current rate for the past 6 months. Controls had smoked between one and 100 cigarettes in their life-time, but never regularly. Participants also rated, retrospectively, pleasurable and displeasurable sensations experienced when they first smoked. We tested for associations between smoking phenotypes and the top 25 SNPs tested for association with nicotine dependence in a previous study. Findings A non-synonymous coding SNP in CHRNA5, rs16969968, was associated with case status [odds ratio (OR) = 1.5, P = 0.01] and, in Caucasians, with experiencing a pleasurable rush or buzz during the first cigarette (OR = 1.6, P = 0.01); these sensations were associated highly with current smoking (OR = 8.2, P = 0.0001). Conclusions We replicated the observation that the minor allele of rs16969968 affects smoking behavior, and extended these findings to sensitivity to smoking effects upon experimentation. While the ability to test genetic associations was limited by sample size, the polymorphism in the CHRNA5 subunit was shown to be associated significantly with enhanced pleasurable responses to initial cigarettes in regular smokers in an a priori test. The findings suggest that phenotypes related to subjective experiences upon smoking experimentation may mediate the development of nicotine dependence.

Replication of the latent class structure of Attention-Deficit/Hyperactivity Disorder (ADHD) subtypes in a sample of Australian twins

BACKGROUND Previous efforts to subtype Attention-Deficit/Hyperactivity Disorder (ADHD) using latent class analysis (LCA) applied to DSM-IV symptom profiles of adolescent female twins from Missouri (USA) have identified distinct classes within the domains of inattention, hyperactivity-impulsivity and combined-type problems. The objective of the current report is to determine if the latent class structure of ADHD subtypes can be replicated in a culturally distinct sample of female and male Australian twins. METHOD LCA was applied to parent-report DSM-IV ADHD symptom profiles of N=2,848 child and adolescent Australian twins and compared to North American findings. Separate models were fitted for females (N= 1,432) and males (N= 1,416). RESULTS The most congruent latent ADHD classes across samples included a non-symptomatic class, three mild-moderate and two severe classes. Also present within samples was a rare hyperactive-impulsive class and a unique class, the structure of which was idiosyncratic across samples. Mean symptom endorsement and individual symptom endorsement probabilities for each of the stable classes were similar across samples. Consistent with previous findings, there was substantial overlap between the DSM-IV inattentive and combined subtypes with the severe inattentive and severe combined latent classes. However, DSM-IV inattentive and combined subtypes were distributed over several latent classes in each sample, and a substantial proportion of individuals with no DSM-IV diagnosis were also assigned to these severe classes. CONCLUSIONS Results from LCA using an Australian twin sample replicate six of the eight latent class subtypes previously reported using Missouri female twins and extend the findings to male twins. LCA and DSM-IV systems of ADHD classification identify different phenotypic groups, and the basis of this disparity merits further investigation.

Discrimination of DSM-IV and Latent Class Attention-Deficit/Hyperactivity Disorder Subtypes by Educational and Cognitive Performance in a Population-Based Sample of Child and Adolescent Twins

OBJECTIVE Despite the general use of DSM-IV attention-deficit/hyperactivity disorder (ADHD) subtypes, there is controversy over the optimal phenotyping strategy for this disorder.This report contrasts two ADHD subtyping approaches on the prediction of cognitive function and educational achievement. METHOD ADHD subtypes were determined using DSM-IV and latent class approaches for a population sample of 1,154 child and adolescent twins using parent report data. Twins completed cognitive and achievement testing and parents reported on school grades, special education placement, and history of being held back in school. RESULTS The DSM-IV primarily inattentive and combined subtype ADHD groups showed significant deficits in cognitive and achievement testing, worse grades, and increased use of special education resources compared with the primarily hyperactive/impulsive subtype and no-ADHD groups. Clinically relevant and less severe latent class ADHD subtypes were also associated with deficits in cognitive and achievement testing, grades, and special education use. CONCLUSIONS DSM-IV primarily inattentive and combined subtypes of ADHD have similar significant patterns of cognitive and academic dysfunction in the general population. Latent class-defined ADHD subtypes also have patterns of serious cognitive and achievement deficits.