A Genome-Wide Linkage Scan for Distinct Subsets of Schizophrenia Characterized by Age at Onset and Neurocognitive Deficits

Yin-Ju Lien,Wei J Chen,Ming T Tsuang,Hai-Gwo Hwu,Chih-Min Liu,Po-Chang Hsiao,Stephen V Faraone,Christian Schönbach

doi:10.1371/journal.pone.0024103

Abstract

BackgroundAs schizophrenia is genetically and phenotypically heterogeneous, targeting genetically informative phenotypes may help identify greater linkage signals. The aim of the study is to evaluate the genetic linkage evidence for schizophrenia in subsets of families with earlier age at onset or greater neurocognitive deficits.MethodsPatients with schizophrenia (n = 1,207) and their first-degree relatives (n = 1,035) from 557 families with schizophrenia were recruited from six data collection field research centers throughout Taiwan. Subjects completed a face-to-face semi-structured interview, the Continuous Performance Test (CPT), the Wisconsin Card Sorting Test, and were genotyped with 386 microsatellite markers across the genome.ResultsA maximum nonparametric logarithm of odds (LOD) score of 4.17 at 2q22.1 was found in 295 families ranked by increasing age at onset, which had significant increases in the maximum LOD score compared with those obtained in initial linkage analyses using all available families. Based on this subset, a further subsetting by false alarm rate on the undegraded and degraded CPT obtained further increase in the nested subset-based LOD on 2q22.1, with a score of 7.36 in 228 families and 7.71 in 243 families, respectively.ConclusionWe found possible evidence of linkage on chromosome 2q22.1 in families of schizophrenia patients with more CPT false alarm rates nested within the families with younger age at onset. These results highlight the importance of incorporating genetically informative phenotypes in unraveling the complex genetics of schizophrenia.

Highlights

And twin studies have indicated that schizophrenia has a strong genetic basis [1]
This study aimed to evaluate the genetic linkage evidence for empirically derived subtypes of schizophrenia by applying ordered subset linkage analyses in a large sample of families of siblings coaffected with schizophrenia, which consisted mainly of a single ethnic group [21]
On the basis of the adjusted z scores, the affected siblings had poorer performance across all of the indices that were based on the correctness of the response on both the Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST) in comparison with the normative data

Summary

Introduction

And twin studies have indicated that schizophrenia has a strong genetic basis [1]. Previous genetic linkage and association studies have not conclusively detected susceptibility loci and genetic variants for schizophrenia [2,3]. The current diagnostic schemes may not capture the most heritable features of schizophrenia. To overcome these obstacles, using genetically informative phenotypes has been advocated since this may reduce heterogeneity or represent the more direct effects of underlying susceptibility genes [4]. As schizophrenia is genetically and phenotypically heterogeneous, targeting genetically informative phenotypes may help identify greater linkage signals. The aim of the study is to evaluate the genetic linkage evidence for schizophrenia in subsets of families with earlier age at onset or greater neurocognitive deficits

Objectives

Methods

Results

Conclusion