Schizophrenia (SCZ) and bipolar affective disorder (BPAD) (formerly termed manic-depressive illness) are severe, disabling psychiatric illnesses that feature promi- nently in the top ten causes of disability worldwide (Lopez and Murray 1998). Each will affect about 1% of the pop- ulation in their lifetime. The cost of providing treatment for mental illness in the UK National Health Service is es- timated at 10% of total expenditure. The total costs (med- ical, social, economic) are estimated at £32 billion per an- num for the population of 50 million in England (Bird 1999; see also www.mentalhealth.org.uk). World Health Organization predictions indicate that major depression will be second only to heart disease in terms of disability- adjusted life years (DALYs) by 2020 (Lopez and Murray 1998). Research into the causes of these devastating dis- orders and the development of improved interventions is a high scientific, social, individual, and public health prior- ity. Unfortunately, these remain Cinderella disorders com- pared to cancer and heart disease, both in terms of gov- ernmental and societal recognition and national and international research support. Despite their high preva- lence and, indeed, decades of neuroscience research, little is known with certainty about their cellular and molecular bases. Consequently, treatments remain largely empirical and palliative. This apparent impasse, however, justifies neither complacency nor despondency, because the one consistent, replicable finding is that family, twin, and adoption studies demonstrate a major genetic component in both SCZ and BPAD (Merikangas and Risch 2003). A decade ago only a handful of genes for monogenic disor- ders had been positionally cloned through linkage studies. Over the past five years, as the Human Genome Project and associated tools have developed, that number has soared to over 1000. As the Human Genome Project passes from formal completion to full development as a universal biological tool, we can expect accelerated progress in tackling the much more difficult task of genet- ically dissecting the common complex disorders including major mental illness. EVIDENCE FOR A GENETIC COMPONENT TO SCZ AND BPAD The risk to a first-degree relative of a person affected by SCZ or BPAD is an order of magnitude higher than that of the general population (from ~1% to 10–15% life- time risk for each disorder) (Kendler and Diehl 1993; Merikangas and Risch 2003). Further evidence for the high heritability of SCZ and of BPAD comes from twin and adoption studies. Concordance rates for monozygotic twins are around 50% for SCZ and 60–80% for BPAD. Importantly, these concordance rates are much higher than for dizygotic twins (10–15%), and the biological risk is unaffected by adoption. Several chromosomal regions that may harbor susceptibility genes for SCZ and for BPAD have been identified by a range of genetic strate- gies (Owen et al. 2000; Potash and DePaulo 2000; Riley and McGuffin 2000). There is also growing evidence that relatives of sufferers are at higher risk of other psychiatric diagnoses within the schizophrenia–affective disorder spectrum (Kendler et al. 1998; Wildenauer et al. 1999; Berrettini 2000; Valles et al. 2000). This suggests that some genetic risk factors may contribute to a range of psychotic symptoms that cross the traditional diagnostic boundaries of SCZ and affective disorders. In part, this may reflect the fact that diagnosis of psychiatric illness is an imprecise science; psychiatric phenotypes are almost entirely based on profiles of behavioral indices and com- munication patterns. The use of standardized diagnostic criteria (such as the Diagnostic and Statistical Manual of Mental Disorders, DSM-IV, published by the American Psychiatric Association, and The ICD-10 Classification of Mental Health and Behavioural Disorders, published by the World Health Organization) has ensured good re- producibility of diagnoses between researchers, but there is wide overlap of symptoms between the diagnostic cat- egories of SCZ, BPAD, and recurrent, major (unipolar) depression. In the absence of reliable biological or ge- netic markers specific for SCZ or BPAD, the validity of existing classification remains uncertain. It would be a major advance if genetic studies yielded molecular diag- nostic methods that could not only resolve some of the present uncertainties in psychiatric diagnosis, but also in- form treatment choice and disease prognosis. Until such time, we can only speculate that variability in individual diagnoses reflects a combination of genetic (and possibly allelic) heterogeneity, polygenic inheritance, and varia- tion in individual life trajectories/environmental expo- sures. Nevertheless, post-genome science most certainly offers the best hope for determining the biological basis Genetics of Schizophrenia and Bipolar Affective Disorder: Strategies to Identify Candidate Genes D.J. PORTEOUS,* K.L. EVANS,* J.K. MILLAR ,* B.S. PICKARD,* P.A. THOMSON,* R. JAMES,* S. MACGREGOR, † N.R. WRAY,* P.M. VISSCHER, † W.J. MUIR, ‡ AND D.H. BLACKWOOD ‡ *Medical Genetics Section, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, EH4 2XU; † Institute of Cell, Animal and Population Biology, Ashworth Laboratories, School of Biology, The University of Edinburgh, The King’s Buildings, Edinburgh, Scotland, EH9 3JT; ‡ Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, Scotland, EH10 5HF Cold Spring Harbor Symposia on Quantitative Biology, Volume LXVIII. © 2003 Cold Spring Harbor Laboratory Press 0-87969-709-1/04. 383