Erik G. Jönsson

Common variants conferring risk of schizophrenia

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Common Variants at VRK2 and TCF4 Conferring Risk of Schizophrenia

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).

Expanding the range of ZNF804A variants conferring risk of psychosis

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10−8. In this study, using 5164 schizophrenia cases and 20u2009709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39u2009481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders).

Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: An association study†

Recent meta‐analyses of the methylenetetrahydrofolate reductase gene (MTHFR) have suggested association between two of its functional single gene polymorphisms (SNPs; C677T and A1298C) and schizophrenia. Studies have also suggested association between MTHFR C677T and A1298C variation and bipolar disorder. In a replication attempt the MTHFR C677T and A1298C SNPs were analyzed in three Scandinavian schizophrenia case‐control samples. In addition, Norwegian patients with bipolar disorder were investigated. There were no statistically significant allele or genotype case‐control differences. The present Scandinavian results do not verify previous associations between the putative functional MTHFR gene polymorphisms and schizophrenia or bipolar disorder. However, when combined with previous studies in meta‐analyses there is still evidence for association between the MTHFR C677T polymorphism and schizophrenia. Additional studies are warranted to shed further light on these relationships.

The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: A multi-centre case–control study and meta-analysis†‡

Serotonin (5‐hydroxytryptamin; 5‐HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5‐monooxygenase; TPH) is the rate‐limiting enzyme in the biosynthesis of 5‐HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (Pu2009=u20090.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (Pu2009=u20090.84). A systematic literature review and meta‐analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07–1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I2u2009=u20090.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (ORu2009=u20090.96 [0.80–1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.

Cortical folding in Broca's area relates to obstetric complications in schizophrenia patients and healthy controls

BACKGROUNDnThe increased occurrence of obstetric complications (OCs) in patients with schizophrenia suggests that alterations in neurodevelopment may be of importance to the aetiology of the illness. Abnormal cortical folding may reflect subtle deviation from normal neurodevelopment during the foetal or neonatal period. In the present study, we hypothesized that OCs would be related to cortical folding abnormalities in schizophrenia patients corresponding to areas where patients with schizophrenia display altered cortical folding when compared with healthy controls.nnnMETHODnIn total, 54 schizophrenia patients and 54 healthy control subjects underwent clinical examination and magnetic resonance image scanning on a 1.5 T scanner. Information on OCs was collected from original birth records. An automated algorithm was used to calculate a three-dimensional local gyrification index (lGI) at numerous points across the cortical mantle.nnnRESULTSnIn both schizophrenia patients and healthy controls, an increasing number of OCs was significantly related to lower lGI in the left pars triangularis (p<0.0005) in Brocas area. For five other anatomical cortical parcellations in the left hemisphere, a similar trend was demonstrated. No significant relationships between OCs and lGI were found in the right hemisphere and there were no significant case-control differences in lGI.nnnCONCLUSIONSnThe reduced cortical folding in the left pars triangularis, associated with OCs in both patients and control subjects suggests that the cortical effect of OCs is caused by factors shared by schizophrenia patients and healthy controls rather than factors related to schizophrenia alone.

Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case–control samples†

Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case–control sample (Nu2009=u2009854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case–control sample (Nu2009=u20091,073/2,919). Combining our Scandinavian samples with an Icelandic sample (Nu2009=u2009435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (Nu2009=u20091,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected Pu2009=u20090.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected Pu2009=u20090.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case–control sample (Nu2009=u20091,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.

Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia.

Different lines of evidence indicate that methylenetetrahydrofolate reductase (MTHFR) functional gene polymorphisms, causative in aberrant folate–homocysteine metabolism, are associated with increased vulnerability to several heritable developmental disorders. Opposing views are expressed considering the possible association between MTHFR and susceptibility for schizophrenia. In order to evaluate if age of onset could explain some of this discrepancy we investigated the relationship between two functional MTHFR gene polymorphisms and age at onset in this disorder. Scandinavian patients (nu2009=u2009820) diagnosed with schizophrenia, schizoaffective disorder, and schizophreniform disorder were investigated. Two functional MTHFR single nucleotide polymorphisms (SNPs; rs1801131 and rs1801133) were genotyped and the effect of MTHFR polymorphisms on the age of onset was examined with survival analysis. In an attempt to replicate the findings from the Scandinavian sample, the association between rs1801133 and age at onset was also analyzed in Chinese high‐risk families, with two or more affected siblings (nu2009=u2009243). Among the Scandinavian patients the functional MTHFR SNP rs1801133 (C677T) significantly affected age at onset of schizophrenia in a dose‐dependent manner (Pu2009=u20090.0015), with lower age of onset with increasing numbers of the mutant T‐allele. There was no evidence of rs1801131 (A1298C) affecting age of onset in schizophrenia. Within the Chinese high‐risk families carriers of the MTHFR 677T allele showed earlier age at onset than siblings being homozygous for the wild‐type allele (Pu2009=u20090.008). The MTHFR C677T polymorphism may play a role as a modifying factor for age of onset in schizophrenia.

Is the Gly82Ser polymorphism in the RAGE gene relevant to schizophrenia and the personality trait psychoticism

BACKGROUNDnThe receptor for advanced glycation end products (RAGE) is the main receptor for S100B, an astrogial proinflammatory mediator that has been suggested to be involved in the pathophysiology of schizophrenia. To further elucidate the possible relevance of inflammation for mental functions, we investigated a functional polymorphism in the gene coding for RAGE in relation to personality traits and susceptibility to schizophrenia.nnnMETHODSnWe studied the Gly82Ser polymorphism (rs2070600, 244G>A) in 2 population-based cohorts of middle-aged participants assessed using the Karolinska Scales of Personality. In addition, we compared genotype frequencies between patients with schizophrenia and controls.nnnRESULTSnThe population-based cohorts included 270 women and 247 men, and the case-control study involved 138 patients with schizophrenia and 258 controls. In the population-based cohorts, 82Ser carriers were found to have significantly higher scores for the psychoticism personality trait comprising the detachment and suspicion subscales. The case-control study revealed that the 82Ser allele was significantly more frequent among patients than controls.nnnLIMITATIONSnThis study was limited by the modest sample size and the use of a self-report measure to assess personality traits.nnnCONCLUSIONnOur findings suggest that the proven relation between certain personality traits and schizophrenia can at least to some extent be explained on a genetic level. Also, the activated S100B-RAGE axis may be an underlying cause, not only a consequence, of the disease.

Tyrosine hydroxylase Val81Met polymorphism : lack of association with schizophrenia

Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden, Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Mental Health Center Frederiksberg, Copenhagen University Hospital, Frederiksberg, Denmark, TOP project, Division of Psychiatry, Ullevål University Hospital & Institute of Psychiatry, University of Oslo, Department of Medical Genetics, Ullevål University Hospital, Institute of Psychiatry, University of Oslo, Psykiatrisk institutt, Vinderen and Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway Correspondence to Dr Dimitrios Andreou, MD, Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, R5:00, SE-171 76 Stockholm, Sweden Tel: + 46 8 51772626; fax: + 46 8 346563; e-mail: dimitrios.andreou@sll.se