Common Gene Variants in Schizophrenia Susceptibility with Focus on Neurodevelopment
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AbstractSchizophrenia is a severe multifactorial mental disorder with an important and complex genetic component, and the understanding of the underlying biological mechanisms is limited. Several lines of evidence support that abnormal neurodevelopment is involved, such as cognitive deficits in children who later develop schizophrenia, abnormalities in brain structure in the early phase of disease, and aberrant neuronal distributions. Also, glutamatergic dysfunctions are suggested in the schizophrenia etiology, and glutamate signalling is important during neurodevelopment. Perineuronal nets are extracellular matrix structures involved in brain maturation, which includes the characteristic neural epitope Human Natural Killer-1 (HNK-1).
To investigate if common gene variants important for neurodevelopment are involved in schizophrenia etiology, we used candidate gene-based association studies of tagSNPs spanning thirty genes, genotyped in a large Scandinavian case-control sample (SCOPE). Nineteen, out of the 289 tagSNPs in 18 neuronal migration genes, were nominally significant, and the strongest finding was a tagSNP located in MAM domain containing glycosylphosphatidylinositol anchor 1 (MDGA1), but no findings were significant after correction. Phosphodiesterase 4B (PDE4B) is a Disrupted-in-Schizophrenia-1 (DISC1) interactor, with previously reported genetic associations only in women. Six and 16, out of 40 and 72 PDE4B tagSNPs, were nominally associated with schizophrenia and bipolar disorder, respectively, in the combined samples or in gender-specific subgroups. No findings were significant after correction. However, two of the tagSNPs nominally associated in schizophrenia females had proxies which were nominally associated in the total bipolar disorder sample, and the four SNPs were located in the same block, surrounding the splice site for the PDE4B3 isoform.
Five out of 104 tagSNPs in ten genes involved in perineuronal net formation and HNK-1 biosynthesis, located in beta-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with schizophrenia. The association signal for tagSNPs in one of the LD blocks was replicated by proxy SNPs in a much larger European sample (SGENE-plus).
Six out of 30 tagSNPs in glutamate receptor ionotrophic kainate 3 (GRIK3) were nominally associated, and the best tagSNP were significant after correction, with increased significance in the Swedish subsample, as well as when the risk allele was combined with another tagSNP risk allele. When investigating clinical characteristics, including positive and negative symptom scores, age at onset, and cognitive measures of learning, memory and IQ, for association with a subset of the tagSNPs and genes included in the thesis studies, there were no significant associations after correction. The current results indicate that gene variants involved in neurodevelopment are associated with schizophrenia, which further supports the neurodevelopmental hypothesis.
List of Papers
Paper I. Kähler AK, Djurovic S, Kulle B, Jonsson EG, Agartz I, Hall H, Opjordsmoen S, Jakobsen KD, Hansen T, Melle I, Werge T, Steen VM, Andreassen OA (2008). Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene. American Journal of Medical Genetics: Part B Neuropsychiatric Genetics 147B:1089-100 DOI: 10.1002/ajmg.b.30726
Paper II. Kähler AK, Otnæss MK, Wirgenes KV, Hansen T, Jönsson EG, Agartz I, Hall H, Werge T, Morken G, Mors O, Mellerup E, Dam H, Koefod P, Melle I, Steen VM, Andreassen OA, Djurovic S (2009). Association study of PDE4B Gene Variants in Scandinavian Schizophrenia and Bipolar Disorder multicenter case-control samples. American Journal of Medical Genetics: Part B Neuropsychiatric Genetics [Epub ahead of print] (2010 153B(1):86-96.) DOI: 10.1002/ajmg.b.30958
Paper III. Kähler AK, Djurovic S, Agartz I, Wirgenes KV, Jönsson EG, Hansen T, Hall H, Giegling I, Muglia P, Cichon S, Rietschel M, Pietiläinen OPH, Peltonen L, Bramon E, Collier D, St Clair D, Sigurdsson E, Petursson H, Rujescu D, Gustafsson O, Melle I, Werge T, Steen VM, Matthews RT, Andreassen OA. A Study of Ten Genes in the HNK-1 Pathway and Perineuronal Nets: B3GAT2 is associated with schizophrenia in two large European Multi-Center Case Control Samples. Submitted
Paper IV. Djurovic S, Kähler AK, Kulle B, Jönsson EG, Agartz I, Le Hellard S, Hall H, Jakobsen KD, Hansen T, Melle I, Werge T, Steen VM, Andreassen OA (2009). A possible association between schizophrenia and GRIK3 polymorphisms in a multicenter sample of Scandinavian origin (SCOPE). Schizophrenia Research 107:242-248. DOI: 10.1016/j.schres.2008.10.010