Abstract
BackgroundPrior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants.MethodsWe analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold-truncated product of P-values for each locus.ResultsWhile no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (P emp<2×10−5) based on the minimum P-value and truncated-product methods, respectively.ConclusionsUsing a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci.
Highlights
With a lifetime prevalence of 1 percent and an estimated annual cost of $62.7 billion in the United States [1], schizophrenia (Scz) is a debilitating neuropsychiatric disorder which poses a significant burden to public health
Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia
These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci
Summary
With a lifetime prevalence of 1 percent and an estimated annual cost of $62.7 billion in the United States [1], schizophrenia (Scz) is a debilitating neuropsychiatric disorder which poses a significant burden to public health. Models comprising continuous traits—often extracted in factor analysis of symptom profiles—have been adduced, typically distinguishing positive, negative, disorganization, and affective symptoms [4] One explanation for this variability lies in the existence of more than one putative etiopathogenic mechanism, each imparting susceptibility to a more or less distinct disease subtype or influencing the character of illness dimensionally. In addition to genes which increase susceptibility to more or less distinct clinical subtypes of illness, other genes may influence clinical features of disease in a dimensional fashion, without altering liability to the illness itself. These have previously been described as modifier loci [2]. Association analyses have yet to provide support for any etiologically relevant variants
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