Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene.
Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P < 0.05) in either a genotypic or allelic association test. All of these genes, except transcription factor DLX1, are involved in the adhesion between neurons and radial glial cells. Eight markers obtained nominal significance in both tests, and were located in intronic or 3'UTR regions of adhesion molecule MDGA1 and previously reported SZ candidate RELN. The most significant result was attained for MDGA1 SNP rs9462341 (unadjusted association results: genotypic P = 0.00095; allelic P = 0.010). Several haplotypes within MDGA1, RELN, ITGA3, and ENAH were nominally significant. Further studies in independent samples are needed, including upcoming genome wide association study results, but our data suggest that MDGA1 is a new SZ susceptibility gene, and that altered neuronal migration is involved in SZ pathology.
Kähler
Anna K
AK
TOP Project, Institute of Psychiatry, University of Oslo, Oslo, Norway. a.k.kahler@medisin.uio.no
Djurovic
Srdjan
S
Kulle
Bettina
B
Jönsson
Erik G
EG
Agartz
Ingrid
I
Hall
Håkan
H
Opjordsmoen
Stein
S
Jakobsen
Klaus D
KD
Hansen
Thomas
T
Melle
Ingrid
I
Werge
Thomas
T
Steen
Vidar M
VM
Andreassen
Ole A
OA
D000328:Adult; D000368:Aged; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules; D009457:Neuroglia; D009474:Neurons / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D000091042:Reelin Protein; D012537:Scandinavian and Nordic Countries; D012559:Schizophrenia / Q000235:genetics*
D015815:Cell Adhesion Molecules; C412476:DISC1 protein, human; D058851:GPI-Linked Proteins; C460759:MDGA1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D000091042:Reelin Protein; C000717127:RELN protein, human