A genome-wide scan for modifier loci in schizophrenia.

The purpose of this study was to detect genetic loci that influence clinical features of, but not necessarily susceptibility to, psychotic illness. In the Irish Study of High-Density Schizophrenia Families (n = 270 families, n = 1,408 individuals), subjects with non-affective psychosis were rated using the Operational Criteria Checklist for Psychotic Illness. Factor analysis identified hallucinations, delusions, and negative, manic, and depressive symptom factors. We performed autosomal genome-wide multipoint non-parametric quantitative trait locus linkage analysis, in affected individuals only, using these five factors, as well as age at onset, and course of illness. Determination of empirical significance and correction for multiple testing was implemented using 200 simulated genome scans. We also tested for pleiotropic loci by examining the sums of -log(10)'s of the empirical P values of multiple traits in selected regions. LODs of 2.42 and 2.35 were obtained near D9S934 (9q33.1) and D14S587 (14q24.2), respectively, for course of illness, and of 2.26 between D6S1040-D6S2420 (6q23.1-25.1) and age at onset. No other regions met criteria for suggestive linkage to any one trait. No loci were significant after correction for multiple testing. On 6q, however, the joint linkage of age of onset, course, delusions, and depressive symptoms resulted in a genome-wide P = 0.06. We conclude that genes located near 9q33.1 and 14q24.2 may modify the clinical course and severity of schizophrenia. A gene in 6q may affect several clinical features of illness.