Genome-wide Linkage Analyses for Both Categorical and Quantitative Subphenotypes of Schizophrenia
Date Issued
2009
Date
2009
Author(s)
Lien, Yin-Ju
Abstract
The dissertation is a research of genome-wide linkage analyses for schizophrenia. Three sub-studies were conducted to investigate the susceptibility loci linked with categorical and quantitative subphenotypes. These studies focused on different dimensions of this disorder, including personality traits, clinical manifestation, and neurocognitive performances.tudy I. The Multidimensionality of Schizotypy in Nonpsychotic Relatives of Patients with Schizophrenia and Its Applications in Ordered Subsets Linkage Analysis of Schizophreniahis study aimed to examine the multidimensionality of schizotypy and validate the structure using ordered subset linkage analyses on information from both relatives’ schizotypy and probands’ schizophrenia symptoms. A total of 203 and 1,310 nonpsychotic first-degree relatives from simplex and multiplex schizophrenia families, respectively, were interviewed with the Diagnostic Interview for Genetic Studies, which contains a modified Structured Interview for Schizotypy. Using Mplus program with categorical factor indicators, a four-factor model (Negative Schizotypy, Positive Schizotypy, Interpersonal Sensitivity, and Social Isolation/Introversion) was extracted by exploratory factor analysis from relatives of simplex families and was confirmed in relatives of multiplex families. The validity of each factor was supported by distinct linkage findings resulting from ordered subset analysis based on different combinations of schizophrenia-schizotypy factors. Six chromosomal regions with significant increase in nonparametric linkage z score (NPL-Z) were found as follows: 15q21.1 (NPL-Z = 3.60) for Negative Schizophrenia-Negative Schizotypy, 10q22.3 (NPL-Z = 3.83) and 15q21.3 (NPL-Z = 3.36) for Negative Schizophrenia-Social Isolation/Introversion, 5q14.2 (NPL-Z = 3.20) and 11q23.3 (NPL-Z = 3.31) for Positive Schizophrenia-Positive Schizotypy, and 4q32.1 (NPL-Z = 3.31) for Positive Schizophrenia-Interpersonal Sensitivity. The greatest NPL-Z of 3.83 on 10q22.3 in the subset was significantly higher than the greatest one of 2.88 in the whole sample (empirical p value = 0.04). We concluded that a consistent four-factor model of schizotypy could be derived in non-psychotic relatives across families of patients with different genetic loadings in schizophrenia. Their differential relations to linkage signals have etiological implications and provide further evidence for their validity.tudy II. Genetic Linkage Evidence for Distinct Subtypes of Schizophrenia Characterized by Age at Onset and Neurocognitive Deficitss schizophrenia is genetically and phenotypically heterogeneous, targeting subphenotypes with possible greater genetic loadings may help reveal a more homogeneous subset of families with greater linkage signals. This study aimed to evaluate the genetic linkage evidence for schizophrenia in subsets of families using earlier age at onset or greater neurocognitive deficits as subphenotypes. Patients with schizophrenia and their first-degree relatives recruited from six data collection research center throughout Taiwan. The sample comprised 1,207 affected individuals and 1,035 unaffected individuals of Han Chinese ethnicity from 557 sib-pair families co-affected with DSM-IV schizophrenia. 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. A series nested ordered subset genome-wide linkage analyses were conducted in this study. Four chromosomal regions (2q22.1, 8q13.1, 8q21.1, and 9p13.3 ) had significant increases in maximum nonparametric linkage z (NPL-Z) scores and reached genome-wide significance in subsets of families of patients with schizophrenia characterized by age at onset or neurocognitive deficits compared with those obtained in initial linkage analyses using all available families. A maximum NPL-Z score of 4.12 at 2q22.1 was found in 295 families ranked by increasing age at onset. 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 NPL-Z on 2q22.1, with a score of 5.36 in 228 families and 5.50 in 243 families, respectively, reaching genome-wide significance. We found strong evidence of linkage on chromosome 2q22.1 in families of schizophrenia patients with younger age at onset and more CPT false alarm rates. We also found evidence of linkage on 8q13.1, 8q21.1, and 9p13.3 in families with particular neurocognitive deficits. These results highlight the importance of incorporating genetic-related subphenotypes in unraveling the complex genetics of schizophrenia.tudy III. A Genome-wide Scan for Quantitative Trait Loci Influencing Neurocognitive Phenotypes for Schizophreniaeurocognitive impairment is the core symptoms of schizophrenia. Genetic studies of such traits may help to elucidate the biological pathways underlying familial liability to schizophrenia. This study aimed to identify regions containing susceptibility loci for the neurocognitive performances in schizophrenia. The sample comprised 1,207 affected individuals and 1,035 unaffected individuals of Han Chinese ethnicity from 557 sib-pair families co-affected with DSM-IV schizophrenia. 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. A series of autosomal genome-wide multipoint non-parametric quantitative trait linkage (QTL) analysis were performed in affected individuals only. Determination of genome-wide empirical significance was implemented using 1,000 simulated genome scans. Results for nonparametric linkage z (NPL-Z) scores greater than 3.0 were found on 5q, 6q, and 12q for particular CPT indices, respectively. Two linkage peaks reached genome-wide significance: NPL-Z scores of 3.32 for undegraded CPT hit rate on 12q24.32 at marker D12S2078 (genome-wide empirical p = 0.03) and NPL-Z scores of 3.28 (genome-wide empirical p = 0.046) on 5q14.2 at marker D5S641for degraded CPT reaction time. The identification of quantitative trait locus 12q24.32 has seldom been implicated in previous linkage studies of schizophrenia, while 5q14.2 overlaps the chromosomal region reported in our recent linkage studies for a subset of schizophrenia families with Positive Schizophrenia-Positive Schizotypy. The differential linkage results may inform functional hypotheses in further genetic analyses for schizophrenia.
Subjects
Schizophrenia
Schizotypy
Age at onset
Neurocognitive deficits
Genome-wide linkage analyses
Ordered subset analyses
Quantitative trait linkage analyses
Type
thesis
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