Brief Report Cognitive endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4 Bipolar disorder and major depressive disorder are common neuropsychiatric illnesses. The underlying brain pathophysiology of these phenotypes is, as yet, not well understood. Heritability estimates of over 80% for bipolar disorder and 40% for major depression indicate a substantial genetic compo- nent (1, 2). Genome-wide and candidate gene association studies of both common polymor- phisms and rare coding variants support an over- lap in risk genes for these disorders and suggest the disruption of shared neurobiological pathways and neural processes (3–5). Neuropsychological impairment is well described for these patient populations and impaired function in specific cognitive domains such as executive function and memory is a well-established feature Drysdale E, Knight HM, McIntosh AM, Blackwood DHR. Cognitive endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4. Bipolar Disord 2013: 15: 215–222. Ó 2013 John Wiley & Sons A ⁄ S. Published by Blackwell Publishing Ltd. Objectives: We studied cognitive function in high-risk relatives belonging to a single extended family showing linkage of bipolar disorder to a locus on chromosome 4. High-risk relatives were defined as those that carried the risk haplotype of polymorphic markers, identified in a previous linkage study. This family provided a rare opportunity to characterize a neuropsychological endophenotype in a homogeneous sample of relatives with a common genetic risk factor. Methods: Fifteen family members carrying the risk haplotype (eight diagnosed with bipolar disorder or depression and seven with no psychiatric diagnosis), unrelated patients with bipolar disorder (n = 36) and major depressive disorder (n = 40), and healthy control subjects (n = 33) were administered the California Verbal Learning Test, Verbal Fluency Test, Hayling Sentence Completion Test, and Brixton Spatial Anticipation Test to assess verbal memory, verbal fluency, and executive function. Results: Compared with healthy controls, family members carrying the risk haplotype were impaired in indices of memory and executive function. There were no significant differences between unaffected and affected haplotype-carrying family members in any cognitive measure. Pronounced deficits in the encoding stage of verbal memory and category verbal fluency were evident in individuals with the risk haplotype. Conclusions: Verbal learning and semantic verbal fluency impairments may represent a cognitive endophenotype for both bipolar disorder and major depression in relatives of bipolar disorder patients, as impairment was also present in high-risk relatives who had not developed any affective disorder symptoms. These findings suggest that impairment in semantic organization may be linked to the genetic aetiology of bipolar disorder. Emma Drysdale, Helen M Knight* 1 , Andrew M McIntosh and Douglas HR Blackwood Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK *Present address: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. ED and HMK contributed equally to this work. doi: 10.1111/bdi.12040 Key words: bipolar disorder – chromosome 4 – cognition – depression – genetic susceptibility – haplotype Received 16 August 2011, revised and accepted for publication 13 October 2012 Corresponding author: Douglas HR Blackwood, Ph.D., FRCPsych, FRCP Division of Psychiatry University of Edinburgh Royal Edinburgh Hospital Edinburgh EH10 5HF UK Fax: 0131-537-6508 E-mail: d.blackwood@ed.ac.uk Bipolar Disorders 2013: 15: 215–222 Ó 2013 John Wiley and Sons A/S Published by Blackwell Publishing Ltd. BIPOLAR DISORDERS 215