Genome-wide Association Study Identifies SESTD1 as a Novel Risk Gene for Lithium Responsive Bipolar Disorder

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10-8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

Postpartum Psychosis in Bipolar Disorder: No Association with Personality, Cognitive Style and Temperament

Background and Aims: Bipolar disorder has been associated with a number of personality traits, cognitive styles and affective temperaments. Women who have bipolar disorder are at increased risk of experiencing postpartum psychosis, however no previous research has investigated these traits in relationship to postpartum episodes. Our aim was to establish whether aspects of personality, cognitive style and affective temperament, that have been associated with bipolar disorder, confer vulnerability to postpartum psychosis over and above their known association with bipolar disorder. Methods: Participants were 552 parous women with DSM-IV bipolar I disorder recruited into the Bipolar Disorder Research Network (www.bdrn.org). Postpartum psychosis group: lifetime episode of postpartum psychosis within 6 weeks of delivery (N = 284). Non-postpartum psychosis group: no history of any perinatal mood episodes (N = 268). Bipolar disorder-associated personality traits (neuroticism, extraversion, schizotypy and impulsivity), cognitive styles (low self-esteem and dysfunctional attitudes) and affective temperaments were measured using well validated self-report questionnaire measures. Results: After controlling for key demographic, clinical and pregnancy-related variables, and measures of current mood state, there were no statistically significant differences between the postpartum psychosis group and non-postpartum psychosis group on any of the personality, cognitive style or affective temperament measures. Conclusions: Personality traits, cognitive styles and affective temperaments associated with the bipolar disorder diathesis in general were not associated with the onset of postpartum psychosis specifically. We have found no evidence that these traits should play a key role when evaluating risk of postpartum psychosis in women with bipolar I disorder considering pregnancy.