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Linkage Analyses in the Portuguese Island Cohort (PIC)

In our earlier work, prior to designing the GPC, we focused on multiplex families with more than one affected member ascertained from a homogeneous population of Portuguese descent in the Azores and Madeira Islands. The islands are geographically isolated from Portugal and from each other, so the first settlers some 500 years ago founded a population that developed in a genetically isolated fashion.9 Our Portuguese Island Cohort (PIC) study ascertained individuals suffering with either schizophrenia or bipolar disorder and their family members. Subjects were carefully characterized using a Portuguese-language version of the Diagnostic Interview for Genetic Studies (DIGS), and all diagnoses were made according to DSM-IV criteria.10

In 2004, our research group, along with investigators at the Broad Institute, discovered a region on chromosome 5q31-5q35 with a nonparametric linkage score (NPL) of 3.28 in the Portuguese population sample.11 This finding was replicated in the PIC bipolar population with psychosis.11 In a more recent analysis of these same families, we confirmed the main linkage peak on 5q at 149.06-158.84 and identified an additional and much narrower one at 146.4-148 MB.12 The latter peak had considerably higher LODs and a more telomeric peak, thus decreasing the probability of false-positive linkage. Similar findings were observed for bipolar disorder, and evidence for potentially shared risks between the bipolar and schizophrenia phenotypes was also found.12

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