title: Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder.
abstract: There is significant evidence that altered dopamine activity plays a role in seasonal affective disorder (SAD). The current study examined three separate genetic hypotheses for SAD related to the 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), a variant associated with decreased affinity for dopamine. We examined the possible contribution of 7R to the overall expression of SAD, attention deficit disorder (ADD) comorbidity, and body weight regulation. As part of an ongoing genetic study of increased eating behavior and mood in female subjects, 108 women with winter SAD and carbohydrate craving/weight gain were administered the Wender-Utah Rating Scale to measure childhood ADD symptomatology, and a questionnaire to assess maximal lifetime body mass index (BMI). To test for an association between 7R and the categorical diagnosis of SAD, the transmission disequilibrium test (TDT) was used in a subsample of probands providing familial DNA. Standard parametric tests were used to compare childhood ADD symptoms and maximal lifetime BMI across the two genotypic groups defined by the presence or absence of 7R. The TDT found no initial evidence for an association between 7R and the categorical diagnosis of SAD. However, 7R carriers reported significantly greater inattention and dysphoria in childhood (p=0.01 and 0.001, respectively) and a higher maximal lifetime BMI (p=0.007) than did probands without this allele. Furthermore, excluding probands with extreme obesity (maximal BMI >40), a strong correlation was found linking childhood inattentive symptoms and maximal lifetime BMI (r=0.35, p=0.001). In overeating women with SAD, the 7R allele of DRD4 may be associated with a unique developmental trajectory characterized by attentional deficits and dysphoria in childhood and mild to moderate obesity in adulthood. This developmental course may reflect different manifestations of the same underlying vulnerability related to central dopamine dysfunction. Given the possibility of population stratification when studying genotype/phenotype relationships, future use of genomic controls and replication of our findings in other overeating and/or ADD populations are needed to confirm these initial results.
authors.affiliation: Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Canada. robert_levitan@camh.net
authors.forename: R D
authors.initials: RD
authors.lastname: Levitan
authors.forename: M
authors.initials: M
authors.lastname: Masellis
authors.forename: R W
authors.initials: RW
authors.lastname: Lam
authors.forename: P
authors.initials: P
authors.lastname: Muglia
authors.forename: V S
authors.initials: VS
authors.lastname: Basile
authors.forename: U
authors.initials: U
authors.lastname: Jain
authors.forename: A S
authors.initials: AS
authors.lastname: Kaplan
authors.forename: S
authors.initials: S
authors.lastname: Tharmalingam
authors.forename: S H
authors.initials: SH
authors.lastname: Kennedy
authors.forename: J L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000097:blood / Q000150:complications / Q000235:genetics*; D015992:Body Mass Index; D001835:Body Weight; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005163:Factor Analysis, Statistical; D005260:Female; D005838:Genotype; D006801:Humans; D006963:Hyperphagia / Q000097:blood / Q000209:etiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000097:blood / Q000235:genetics*; D050638:Receptors, Dopamine D4; D012091:Repetitive Sequences, Nucleic Acid; D016574:Seasonal Affective Disorder / Q000097:blood / Q000150:complications / Q000235:genetics*
chemical_list: C493599:DRD4 protein, human; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4