Comprehensive gene-based association study of a chromosome 20 linked region implicates novel risk loci for depressive symptoms in psychotic illness.
BACKGROUND
Prior 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.


METHODS
We 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.


RESULTS
While 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.


CONCLUSIONS
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.
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
T Bernard
TB
Bigdeli
Brion S
BS
Maher
Zhongming
Z
Zhao
Edwin J C G van den
EJ
Oord
Dawn L
DL
Thiselton
Jingchun
J
Sun
Bradley T
BT
Webb
Richard L
RL
Amdur
Brandon
B
Wormley
Francis A
FA
O'Neill
Dermot
D
Walsh
Brien P
BP
Riley
Kenneth S
KS
Kendler
Ayman H
AH
Fanous
D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D003198:Computer Simulation; D003863:Depression / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011618:Psychotic Disorders / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D012307:Risk Factors
D005819:Genetic Markers