Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene.
BACKGROUND
Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes.


METHODS
Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects.


RESULTS
We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers.


CONCLUSIONS
These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia.
Puri
Vinay
V
Molecular Psychiatry Laboratory, Department of Mental Health Sciences, University College London Medical School, London, UK.
McQuillin
Andrew
A
Choudhury
Khalid
K
Datta
Susmita
S
Pimm
Jonathan
J
Thirumalai
Srinivasa
S
Krasucki
Robert
R
Lawrence
Jacob
J
Quested
Digby
D
Bass
Nicholas
N
Moorey
Helen
H
Morgan
Jenny
J
Punukollu
Bhaskar
B
Kandasami
Gomathinayagam
G
Curtis
David
D
Gurling
Hugh
H
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods; D002878:Chromosomes, Human, Pair 1; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020710:RGS Proteins / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human; D020710:RGS Proteins; C098799:RGS4 protein; D017346:Protein Serine-Threonine Kinases