Cross - Disorder Genomewide

psychotic disorders and bipolar disorder (8) and between bipolar disorder and major depressive disorder (9). Although family and twin studies can estimate the shared heritability across disorders, they cannot identify the genetic loci contributing to this overlap. To date, evidence implicating specifi c chromosomal regions and genes in the shared liability to psychotic and mood disorders has largely been limited to linkage and candidate gene association studies. Some of the regions with the strongest linkage evidence for schizophrenia are also among regions most strongly linked to bipolar disorder (10–12), although simulations suggest that such overlap could easily occur by chance (7). Several chromosomal microdeletions have also been associated with both mood and psychotic disorders. The balanced translocation ([1, 11][q42;q14.3]) that disrupts the DISC1 gene was fi rst identifi ed because of its cosegregation with a broad phenotype comprising schizophrenia, bipolar disorder, and recurrent major depressive disorder (13). The 22q11 microdeletion responsible for velocardiofacial syndrome also appears to confer increased risk of both psychotic and mood disorders (14, 15). Candidate gene studies have also found association Family and twin studies have established that schizophrenia, bipolar disorder, and major depressive disorder are familial and heritable phenotypes and that genetic factors are the most robustly validated risk factors for each disorder (1–3). However, several fi ndings have called into question whether these disorders are etiologically distinct. First, several key clinical features, including psychosis, neurocognitive impairment, and suicidality, may be observed in all three disorders. Second, genetic epidemiologic studies have documented that schizophrenia, bipolar disorder, and major depressive disorder share familial and genetic determinants. Family studies have shown familial coaggregation for schizophrenia and bipolar disorder (4–6) as well as bipolar disorder and major depressive disorder (1). In a population-based study of more than 2 million families, Lichtenstein et al. (7) demonstrated increased risks of schizophrenia among relatives of bipolar disorder probands and increased risks of bipolar disorder among relatives of schizophrenia probands. Comorbidity between the disorders was mainly attributable to overlapping genetic infl uences. Twin studies have similarly documented substantial shared genetic variance between Jie Huang, M.D., M.S., M.P.H.