Jane Scourfield

Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT)

The human serotonin transporter gene (hSERT) is a strong candidate for involvement in the pathogenesis of mood disorder and, using a UK Caucasian case-control sample, Collier et al found a significant association between bipolar disorder and the 12 allele of the VNTR polymorphism in intron 2 of this gene. In a European collaborative sample, Collier et al found a significant association between affective disorder and a functional deletion polymorphism in the promoter of hSERT. We have undertaken association studies using these polymorphisms in a British Caucasian sample comprising 171 DSM-IV bipolar probands, 80 DSM-IV major depression probands and 121 unrelated controls matched to bipolar probands for age, sex and ethnicity. We found no association between the promoter deletion and affective disorder but our findings with the VNTR polymorphism are similar to those of Collier and colleagues: we found a significant excess of the 12 repeat allele in bipolar probands (P = 0.031, one-tail) with a suggestion of a gene dosage effect (using genotypes bearing no 12 repeat allele as baseline, the increased risks conferred by genotypes bearing 12 repeat alleles were: heterozygote, OR = 1.24; homozygote, OR = 1.76). Our findings add to the evidence that variation at or near hSERT influences susceptibility to bipolar disorder in the British Caucasian population.

Depressive symptoms in children and adolescents: changing aetiological influences with development

BACKGROUND Evidence suggests that depressive symptoms become increasingly heritable as children grow into adolescence. However, the literature is not entirely consistent in this respect and existing longitudinal twin studies have examined changes within adolescence only. METHOD Parent and self-report questionnaire data were used to examine the genetic and environmental influences on depressive symptoms in a UK sample of 670 twin pairs aged 5-17. Age effects were examined cross-sectionally and longitudinally using data collected over a 3-year period. RESULTS Cross-sectional analyses showed that shared environmental effects had significant influence in younger children but not in adolescence, when depression scores were significantly more heritable. The results of these cross-sectional analyses were supported when two waves of parent-report data collected over three years were analysed. Significant new genetic influences emerged in adolescence but no new shared environmental influences. Some sex differences were found, with girls showing greater genetic influence than boys, but only from parent-report data. CONCLUSIONS These findings support and extend earlier work which has shown increasing genetic influence on depressive symptoms as children grow into adolescence.

Is disabling fatigue in childhood influenced by genes

BACKGROUND Medically unexplained chronic fatigue in childhood may cause considerable disability and (by definition) its cause remains unclear. A study of fatigue in healthy twins has been undertaken to examine whether or not genetic factors play a part. METHOD A questionnaire survey of the main carers of an epidemiological population-based sample of 670 twin pairs who were asked about periods of unexplained and disabling fatigue in their twins. Out of 1340 individuals a period of disabling fatigue was reported for 92 (6.9%). Thirty-three (2.5%) reported disabling fatigue for more than 1 month. Zygosity could be confidently assigned in 98% of the sample providing 278 monozygotic (MZ) and 378 dizygotic (DZ) pairs. These data were analysed using a structural equation modelling approach. RESULTS The results showed that disabling fatigue in childhood is highly familial with an MZ tetrachoric correlation (rMZ) of 0.81 and a DZ tetrachoric correlation (rDZ) of 0.59, for fatigue lasting at least a week. The most acceptable model using Akaikes information criteria, was one containing additive genetic effects (A) and shared environment (C) plus residual (or non-shared) environment (E). For fatigue lasting at least a month rMZ was 0.75 and rDZ 0.47. The most acceptable model included just A and E. However, the role of shared environment could not be conclusively rejected. CONCLUSIONS Unexplained disabling fatigue in childhood is substantially familial. Both genetic and shared environmental factors are worth further exploration in a search for the causes.

Attitudes towards future testing for bipolar disorder susceptibility genes: a preliminary investigation

The discovery of susceptibility genes for the major psychiatric illnesses may lead to the development of presymptomatic and prenatal tests. In a preliminary study we assessed the attitudes of 147 bipolar patients, 90 attendees at their family doctor (GP) and 32 psychiatrists to the possible development of genetic tests for bipolar disorder susceptibility genes. Our results suggest that patients and the public will look favourably on the development of presymptomatic (but not prenatal) testing for bipolar disorder susceptibility genes. Psychiatrists, who will have to administer such tests, appear significantly more cautious.

Genetic Overlap Between Measures of Hyperactivity/Inattention and Mood in Children and Adolescents

OBJECTIVE Evidence suggests that there is substantial comorbidity between attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder in childhood and adolescence. This study aims to investigate the degree to which etiological factors are shared between the symptoms of these significantly heritable disorders. METHOD A twin study design was used to determine to what extent the covariation between the traits of ADHD and depression is genetically or environmentally mediated, based on parental reports. A general community sample of 645 twin pairs aged 5 to 17 years from the Cardiff Study of All Wales and North England Twins project took part in the study. Parent-rated measures of hyperactivity/inattention (Abbreviated Conners Hyperactivity subscale) and depression (Short Mood and Feelings Questionnaire). RESULTS Phenotypes derived from the scales were significantly correlated in both boys and girls. Bivariate structural equation modeling revealed a large overlap in underlying genetic factors (boys, rA = 0.77; girls, rA = 0.67) along with a smaller influence of nonshared environment. CONCLUSIONS These findings suggest that there are common genes conferring liability to both hyperactive/inattentive and depressive traits in children and adolescents. This has implications for future molecular genetic research into ADHD and major depressive disorder. Additionally, it indicates that the comorbid clinical presentation of these disorders may reflect a common genetic pathway.

Do aggressive and non-aggressive antisocial behaviors in adolescents result from the same genetic and environmental effects?

Antisocial behavior (ASB) in adolescents can broadly be separated into two forms; aggressive and non‐aggressive. Both are heritable and it has been suggested that aggressive ASB is more heritable. The extent to which genes contribute to the correlation between the two is unknown. Structural equation modeling was applied to a population‐based twin sample of 258 twins pairs aged 11–18 to estimate the heritability of each form of ASB and to estimate the extent to which the phenotypic correlation was the consequence of shared genes and environmental factors. Non‐shared environment and genetic factors substantially influenced both forms of ASB. The heritability of aggressive (but not non‐aggressive) ASB was significantly higher in girls than in boys. Combining both sexes, a model in which the genetic effects on aggressive and non‐aggressive ASB were identical could be rejected. Our results suggest a partial genetic overlap with a specific genetic effect contributing to the variance of aggressive ASB and a stronger genetic effect on aggression in females than in males.

Human genetics. A father's imprint on his daughter's thinking

Why do women often fare better than men in social situations? The answer, it seems, may be in our genes. Studies of women with Turners syndrome, who have either all or part of one X chromosome missing, indicate that social functioning is influenced by a gene on the X chromosome that is switched off if it is inherited from the mother. This may explain why men (who all inherit their X chromosome maternally) are more susceptible than women to developmental disorders that affect language and social functioning.