-
Mette Nyegaard,
Ditte Demontis,
Britta Boserup Thestrup,
Anne Hedemand,
Karina Meden Sørensen, Thomas Hansen,
Thomas Werge,
David Michael Hougaard,
Robert H Yolken,
Preben Bo Mortensen,
Ole Mors,
Anders D Børglum
[show abstract]
[hide abstract]
ABSTRACT: The human endogenous retrovirus HERV-K18 is located within intron 1 of CD48 on chromosome 1q and is still active in the human genome. Genetic variation in HERV-K18 single-nucleotide polymorphisms (SNPs) has previously been associated with an increased risk of schizophrenia (SZ) and with type 2 diabetes (T2D) among individuals with SZ. Here, we present a replication study of association of two SNPs in HERV-K18 and 19 tagSNPs in CD48 with (a) SZ and (b) T2D in patients with SZ in two Danish samples (total number of cases=750 and controls=1214). No association was found with SZ or with T2D among individuals with SZ for any of the investigated SNPs. However, one HERV-K18 SNP showed a tendency toward an association with T2D in younger SZ patients, in agreement with previous findings, but due to a very low sample size, this result needs to be further investigated.
Psychiatric genetics 04/2012; 22(3):146-8. · 2.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Complex diseases may be associated with combinations of changes in DNA, where the single change has little impact alone. In a previous study of patients with bipolar disorder and controls combinations of SNP genotypes were analyzed, and four large clusters of combinations were found to be significantly associated with bipolar disorder. It has now been found that these clusters may be connected to clinical data.
PLoS ONE 01/2012; 7(9):e44623. · 4.09 Impact Factor
-
Kari M Ersland,
Andrea Christoforou,
Christine Stansberg,
Thomas Espeseth,
Manuel Mattheisen,
Morten Mattingsdal,
Gudmundur A Hardarson, Thomas Hansen,
Carla P D Fernandes,
Sudheer Giddaluru, [......],
Srdjan Djurovic,
Markus M Nöthen,
Marcella Rietschel,
Astri J Lundervold,
Thomas Werge,
Sven Cichon,
Ole A Andreassen,
Ivar Reinvang,
Vidar M Steen,
Stephanie Le Hellard
[show abstract]
[hide abstract]
ABSTRACT: Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked.
At the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample.
Our gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits.
PLoS ONE 01/2012; 7(2):e31687. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The MCHR1 gene encoding the melanin-concentrating hormone receptor 1 is located on chromosome 22q13.2 and has previously been associated with schizophrenia in a study of cases and controls from the Faroe Islands and Scotland. Herein we report an association between variations in the MCHR1 gene and schizophrenia, based on analyses of a larger sample and an increased number of single nucleotide polymorphisms (SNPs) than used in the previous study.
Eighteen SNPs in the MCHR1 gene region were genotyped in a Caucasian case-control sample from Denmark consisting of 390 individuals with schizophrenia and 814 control individuals. Sex-specific analysis and analysis of association with antipsychotic treatment were performed.
Five SNPs in the proximal region of MCHR1 were significantly associated with schizophrenia. The associations seemed to be sex specific, predominantly seen in men where one SNP (rs133073) remained significant (P=0.003) after correction for multiple testing. When combining the P values in the proximal region of MCHR1, the region-wise P value was low (P=0.009) supporting that variations in this part of the gene is associated with schizophrenia. Furthermore, the association was stronger in patients responding to conventional and atypical antipsychotic medication except clozapine.
Our results suggest that MCHR1 may influence schizophrenia susceptibility, in particular among men and patients responding to conventional (nonclozapine) treatment.
Psychiatric genetics 11/2011; 22(2):62-9. · 2.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Depression is accompanied by an inflammatory reaction and activation of cell mediated immunity (CMI) and stressors may induce the cytokine network in humans. The proinflammatory cytokine interleukin-18 (IL-18) is less investigated in depression but highly relevant since it is produced by activated macrophages and expressed in the brain.
The distribution of six polymorphisms in IL10, IL18 and NF was compared between patients with a single episode of depression either preceded by a stressful life event (n=182), or occurring without a prior stressful life event (n=106) and a group of healthy control individuals (n=335).
The major C allele of the IL18 rs187238 and the major G allele of rs1946518 had a significantly higher prevalence among the patients with a stressful life event prior to onset of disease than both patients without a stressful life event and compared with the healthy controls individuals. None of the examined IL10 or NF alleles were differently distributed among these groups.
Data are nominally significant and not resistant to correction for multiple testing.
The major C allele of the IL18 rs187238 and the major G allele rs1946518 have previously been associated with higher expression of IL-18 mRNA. Our data suggest that this genetic trend towards higher IL-18 production may increase the susceptibility to depression in response to stressful life events.
Journal of affective disorders 09/2011; 136(1-2):134-8. · 3.76 Impact Factor
-
Stephan Ripke,
Alan R Sanders,
Kenneth S Kendler,
Douglas F Levinson,
Pamela Sklar,
Peter A Holmans,
Dan-Yu Lin,
Jubao Duan,
Roel A Ophoff,
Ole A Andreassen, [......],
Durk Wiersma,
Dieter B Wildenauer,
Hywel J Williams,
Nigel M Williams,
Brandon Wormley,
Stan Zammit,
Patrick F Sullivan,
Michael C O'Donovan,
Mark J Daly,
Pablo V Gejman
[show abstract]
[hide abstract]
ABSTRACT: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).
Nature Genetics 09/2011; 43(10):969-76. · 35.53 Impact Factor
-
Frank Geller,
Bjarke Feenstra,
Hao Zhang,
John R Shaffer, Thomas Hansen,
Ann-Louise Esserlind,
Heather A Boyd,
Ellen A Nohr,
Nicholas J Timpson,
Ghazaleh Fatemifar, [......],
Robert J Weyant,
Steven M Levy,
Mark Lathrop,
George Davey Smith,
Jeffrey C Murray,
Jes Olesen,
Thomas Werge,
Mary L Marazita,
Thorkild I A Sørensen,
Mads Melbye
[show abstract]
[hide abstract]
ABSTRACT: The sequence and timing of permanent tooth eruption is thought to be highly heritable and can have important implications for the risk of malocclusion, crowding, and periodontal disease. We conducted a genome-wide association study of number of permanent teeth erupted between age 6 and 14 years, analyzed as age-adjusted standard deviation score averaged over multiple time points, based on childhood records for 5,104 women from the Danish National Birth Cohort. Four loci showed association at P<5×10(-8) and were replicated in four independent study groups from the United States and Denmark with a total of 3,762 individuals; all combined P-values were below 10(-11). Two loci agreed with previous findings in primary tooth eruption and were also known to influence height and breast cancer, respectively. The two other loci pointed to genomic regions without any previous significant genome-wide association study results. The intronic SNP rs7924176 in ADK could be linked to gene expression in monocytes. The combined effect of the four genetic variants was most pronounced between age 10 and 12 years, where children with 6 to 8 delayed tooth eruption alleles had on average 3.5 (95% confidence interval: 2.9-4.1) fewer permanent teeth than children with 0 or 1 of these alleles.
PLoS Genetics 09/2011; 7(9):e1002275. · 8.69 Impact Factor
-
Francisco S Roque,
Peter B Jensen,
Henriette Schmock,
Marlene Dalgaard,
Massimo Andreatta, Thomas Hansen,
Karen Søeby,
Søren Bredkjær,
Anders Juul,
Thomas Werge,
Lars J Jensen,
Søren Brunak
[show abstract]
[hide abstract]
ABSTRACT: Electronic patient records remain a rather unexplored, but potentially rich data source for discovering correlations between diseases. We describe a general approach for gathering phenotypic descriptions of patients from medical records in a systematic and non-cohort dependent manner. By extracting phenotype information from the free-text in such records we demonstrate that we can extend the information contained in the structured record data, and use it for producing fine-grained patient stratification and disease co-occurrence statistics. The approach uses a dictionary based on the International Classification of Disease ontology and is therefore in principle language independent. As a use case we show how records from a Danish psychiatric hospital lead to the identification of disease correlations, which subsequently can be mapped to systems biology frameworks.
PLoS Computational Biology 08/2011; 7(8):e1002141. · 5.22 Impact Factor
-
M Rietschel,
M Mattheisen,
F Degenhardt,
Ren|[eacute]| S Kahn,
Don H Linszen,
Jim van Os,
Durk Wiersma,
Richard Bruggeman,
Wiepke Cahn,
Lieuwe de Haan, [......],
N Craddock,
M J Owen,
M C O'Donovan,
A D B|[oslash]|rglum,
D Rujescu,
H Walter,
A Meyer-Lindenberg,
M M N|[ouml]|then,
R A Ophoff,
S Cichon
[show abstract]
[hide abstract]
ABSTRACT: Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11 540; P=3.89 × 10−9, odds ratio (OR)=1.25). This finding was replicated in 23 206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.Keywords: common variation; genome-wide association study; GWAS; imaging genetics; schizophrenia
Molecular Psychiatry 07/2011; 17(9):906-917. · 13.67 Impact Factor
-
Jessica E Van Schijndel,
Martine Van Zweeden,
Karen M J Van Loo,
Srdjan Djurovic,
Ole A Andreassen, Thomas Hansen,
Thomas Werge,
Mette Nyegaard,
Karina Meden Sørensen,
Merete Nordentoft, [......],
Karl-Fredrik Norrback,
Rolf Adolfsson,
Marc De Hert,
Stephan Claes,
Sven Cichon,
Marcella Rietschel,
Markus M Nöthen,
Pekka Kallunki,
Jan T Pedersen,
Gerard J M Martens
[show abstract]
[hide abstract]
ABSTRACT: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor.
We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups.
Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor.
An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors.
Psychiatric genetics 06/2011; 21(3):125-31. · 2.33 Impact Factor
-
Bjarte Håvik,
Stephanie Le Hellard,
Marcella Rietschel,
Helle Lybæk,
Srdjan Djurovic,
Manuel Mattheisen,
Thomas W Mühleisen,
Franziska Degenhardt,
Lutz Priebe,
Wolfgang Maier, [......],
Ingrid Agartz,
Ingrid Melle, Thomas Hansen,
Clive R Bramham,
Markus M Nöthen,
Beth Stevens,
Thomas Werge,
Ole A Andreassen,
Sven Cichon,
Vidar M Steen
[show abstract]
[hide abstract]
ABSTRACT: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia.
Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish case-control samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects.
Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10(-8); odd ratio = .73, 95% confidence interval = .65-.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA.
These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain.
Biological psychiatry 03/2011; 70(1):35-42. · 8.93 Impact Factor
-
Thomas Hansen,
Andrés Ingason,
Srdjan Djurovic,
Ingrid Melle,
Mogens Fenger,
Omar Gustafsson,
Klaus D Jakobsen,
Henrik B Rasmussen,
Sarah Tosato,
Marcella Rietschel, [......],
Sven Cichon,
Roel A Ophoff,
Olli Pietiläinen,
Leena Peltonen,
Markus M Nöthen,
Dan Rujescu,
David St Clair,
David A Collier,
Ole A Andreassen,
Thomas Werge
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia is associated with increased risk of type II diabetes and metabolic disorders. However, it is unclear whether this comorbidity reflects shared genetic risk factors, at-risk lifestyle, or side effects of antipsychotic medication.
Eleven known risk variants of type II diabetes were genotyped in patients with schizophrenia in a sample of 410 Danish patients, each matched with two healthy control subjects on sex, birth year, and month. Replication was carried out in a large multinational European sample of 4089 patients with schizophrenia and 17,597 controls (SGENE+) using Mantel-Haenszel test.
One type II diabetes at-risk allele located in TCF7L2, rs7903146 [T], was associated with schizophrenia in the discovery sample (p = .0052) and in the replication with an odds ratio of 1.07 (95% confidence interval 1.01-1.14, p = .033).
The association reported here with a well-known diabetes variant suggests that the observed comorbidity is partially caused by genetic risk variants. This study also demonstrates how genetic studies can successfully examine an epidemiologically derived hypothesis of comorbidity.
Biological psychiatry 03/2011; 70(1):59-63. · 8.93 Impact Factor
-
Line Olsen, Thomas Hansen,
Srdjan Djurovic,
Eva Haastrup,
Anders Albrecthsen,
Louise K E Hoeffding,
Anna Secher,
Omar Gustafsson,
Klaus D Jakobsen,
Finn C Nielsen,
Henrik Ullum,
Gunnar Morken,
Ingrid Agartz,
Ingrid Melle,
Ulrik Gether,
Ole A Andreassen,
Thomas Werge
[show abstract]
[hide abstract]
ABSTRACT: In two recent studies 10 copy number variants (CNV) were found to be overrepresented either among patients suffering from affective disorders in an Amish family or in the Wellcome Trust Case-Control Consortium study. Here, we investigate if these variants are associated with affective disorders in a combined analysis of three case-control samples from Denmark, Norway and Iceland. A total of 1897 cases (n=1223 unipolar and n=463 bipolar) and 11 231 controls were analyzed for CNVs at the 10 genomic loci, but we found no combined association between these CNVs and affective disorders.
Psychiatric genetics 03/2011; 21(6):319-22. · 2.33 Impact Factor
-
Andrés Ingason,
George Kirov,
Ina Giegling, Thomas Hansen,
Anthony R Isles,
Klaus D Jakobsen,
Kari T Kristinsson,
Louise le Roux,
Omar Gustafsson,
Nick Craddock, [......],
Markus M Nöthen,
Hugh Gurling,
Michael C O'Donovan,
Michael J Owen,
Engilbert Sigurdsson,
Hannes Petursson,
Hreinn Stefansson,
Dan Rujescu,
Kari Stefansson,
Thomas Werge
[show abstract]
[hide abstract]
ABSTRACT: Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10-15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness.
The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis.
Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome.
These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis.
American Journal of Psychiatry 02/2011; 168(4):408-17. · 12.54 Impact Factor
-
Pernille Koefoed,
Ole A Andreassen,
Bente Bennike,
Henrik Dam,
Srdjan Djurovic, Thomas Hansen,
Martin Balslev Jorgensen,
Lars Vedel Kessing,
Ingrid Melle,
Gert Lykke Møller,
Ole Mors,
Thomas Werge,
Erling Mellerup
[show abstract]
[hide abstract]
ABSTRACT: Any given single nucleotide polymorphism (SNP) in a genome may have little or no functional impact. A biologically significant effect may possibly emerge only when a number of key SNP-related genotypes occur together in a single organism. Thus, in analysis of many SNPs in association studies of complex diseases, it may be useful to look at combinations of genotypes. Genes related to signal transmission, e.g., ion channel genes, may be of interest in this respect in the context of bipolar disorder. In the present study, we analysed 803 SNPs in 55 genes related to aspects of signal transmission and calculated all combinations of three genotypes from the 3×803 SNP genotypes for 1355 controls and 607 patients with bipolar disorder. Four clusters of patient-specific combinations were identified. Permutation tests indicated that some of these combinations might be related to bipolar disorder. The WTCCC bipolar dataset were use for replication, 469 of the 803 SNP were present in the WTCCC dataset either directly (n = 132) or by imputation (n = 337) covering 51 of our selected genes. We found three clusters of patient-specific 3×SNP combinations in the WTCCC dataset. Different SNPs were involved in the clusters in the two datasets. The present analyses of the combinations of SNP genotypes support a role for both genetic heterogeneity and interactions in the genetic architecture of bipolar disorder.
PLoS ONE 01/2011; 6(8):e23812. · 4.09 Impact Factor
-
Martin Tesli,
Lavinia Athanasiu,
Morten Mattingsdal,
Anna K Kähler,
Omar Gustafsson,
Bettina K Andreassen,
Thomas Werge, Thomas Hansen,
Ole Mors,
Erling Mellerup,
Pernille Koefoed,
Erik G Jönsson,
Ingrid Agartz,
Ingrid Melle,
Gunnar Morken,
Srdjan Djurovic,
Ole A Andreassen
[show abstract]
[hide abstract]
ABSTRACT: A recent genome-wide association study (GWAS) found significant association between the PALB2 SNP rs420259 and bipolar disorder (BD). The intracellular functions of the expressed proteins from the breast cancer risk genes PALB2 and BRCA2 are closely related. Therefore, we investigated the relation between genetic variants in PALB2 and BRCA2 and BD. Due to increasing evidence of genetic overlap between BD and schizophrenia (SCZ), we also investigated association with SCZ. In a Scandinavian case-control sample (n = 686/2,538) we found the BRCA2 SNP rs9567552 to be significantly associated with BD (Nominal P = 0.00043). Additionally, we replicated the association between PALB2 SNP rs420259 and BD (Nominal P = 0.025). We then combined our sample with another Nordic case-control sample (n = 435/11,491) from Iceland, and added results from the Wellcome Trust Case Control Consortium (WTCCC) (n = 1,868/2,938) and the STEP-UCL/ED-DUB-STEP2 study (n = 2,558/3,274) in a meta-analysis which revealed a P-value of 1.2 × 10(-5) for association between PALB2 SNP rs420259 and BD (n = 5,547/20,241). Neither the PALB2 SNP rs420259 nor the BRCA2 SNP rs9567552 were nominally significantly associated with the SCZ phenotype in our Scandinavian sample (n = 781/2,839). Our findings support PALB2 and BRCA2 as risk genes specifically for BD, and suggest that altered DNA repair related to neurogenesis may be involved in BD pathophysiology. © 2010 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2010; 153B(7):1276-82. · 3.70 Impact Factor
-
Anna K Kähler,
Srdjan Djurovic,
Lars M Rimol,
Andrew Anand Brown,
Lavinia Athanasiu,
Erik G Jönsson, Thomas Hansen,
Omar Gústafsson,
Håkan Hall,
Ina Giegling, [......],
Engilbert Sigurdsson,
Hannes Petursson,
Dan Rujescu,
Ingrid Melle,
Thomas Werge,
Vidar M Steen,
Anders M Dale,
Russell T Matthews,
Ingrid Agartz,
Ole A Andreassen
[show abstract]
[hide abstract]
ABSTRACT: The Human Natural Killer-1 carbohydrate (HNK-1) is involved in neurodevelopment and synaptic plasticity. Extracellular matrix structures called perineuronal nets, condensed around subsets of neurons and proximal dendrites during brain maturation, regulate synaptic transmission and plasticity.
Ten genes of importance for HNK-1 biosynthesis (B3GAT1, B3GAT2, and CHST10) or for the formation of perineuronal nets (TNR, BCAN, NCAN, HAPLN1, HAPLN2, HAPLN3, and HAPLN4) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by genotyping 104 tagSNPs in the Scandinavian Collaboration on Psychiatric Etiology sample (849 cases; 1602 control subjects). Genome-wide association study imputation data from the European SGENE-plus sample (2663 cases; 13,498 control subjects) were used for comparison. The effect of SCZ risk alleles on brain structure was investigated in a Norwegian subset (98 cases; 177 control subjects) with structural magnetic resonance imaging data.
Five single nucleotide polymorphisms (SNPs), located in two adjacent estimated linkage disequilibrium blocks in the first intron of β-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with SCZ (.004 ≤ P(empirical) ≤ .05). The rs2460691 was significantly associated in the comparison sample and in the meta-analysis after correction for all 121 SNP/haplotype tests (P(raw) = 1 × 10(-4); P(corrected) = .018). Increased dosage of the rs2460691 SCZ risk allele was associated with decreased cortical area (p = .002) but not thickness or hippocampal volume. A second SNP (r(2) = .24 with rs10945275), which conferred the highest SCZ risk effect in the Norwegian subset, was also associated with cortical area.
The present results suggest that effects on biosynthesis of the neuronal epitope HNK-1, through common B3GAT2 variation, could increase the risk of SCZ, possibly by decreasing cortical area.
Biological psychiatry 10/2010; 69(1):90-6. · 8.93 Impact Factor
-
Maria Holtze,
Peter Saetre,
Sophie Erhardt,
Lilly Schwieler,
Thomas Werge, Thomas Hansen,
Jimmi Nielsen,
Srdjan Djurovic,
Ingrid Melle,
Ole A Andreassen,
Håkan Hall,
Lars Terenius,
Ingrid Agartz,
Göran Engberg,
Erik G Jönsson,
Martin Schalling
Biological Psychiatry 10/2010; 127(1-3):270-2. · 8.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In high-income countries, administration of antenatal steroids is standard care for women with anticipated preterm labour. However, although >1 million deaths due to preterm birth occur annually, antenatal steroids are not routine practice in low-income countries where most of these deaths occur.
To review the evidence for and estimate the effect on cause-specific neonatal mortality of administration of antenatal steroids to women with anticipated preterm labour, with additional analysis for the effect in low- and middle-income countries.
We conducted systematic reviews using standardized abstraction forms. Quality of evidence was assessed using an adapted GRADE approach. Existing meta-analyses were reviewed for relevance to low/middle-income countries, and new meta-analysis was performed.
We identified 44 studies, including 18 randomised control trials (RCTs) (14 in high-income countries) in a Cochrane meta-analysis, which suggested that antenatal steroids decrease neonatal mortality among preterm infants (<36 weeks gestation) by 31% [relative risk (RR) = 0.69; 95% confidence interval (CI) 0.58-0.81]. Our new meta-analysis of four RCTs from middle-income countries suggests 53% mortality reduction (RR = 0.47; 95% CI 0.35-0.64) and 37% morbidity reduction (RR = 0.63; 95% CI 0.49-0.81). Observational study mortality data were consistent. The control group in these equivalent studies was routine care (ventilation and, in many cases, surfactant). In low-income countries, many preterm babies currently receive little or no medical care. It is plausible that antenatal steroids may be of even greater effect when tested in these settings.
Based on high-grade evidence, antenatal steroid therapy is very effective in preventing neonatal mortality and morbidity, yet remains at low coverage in low/middle-income countries. If fully scaled up, this intervention could save up to 500 000 neonatal lives annually.
International Journal of Epidemiology 04/2010; 39 Suppl 1:i122-33. · 6.41 Impact Factor
-
Andrés Ingason,
Ina Giegling,
Sven Cichon, Thomas Hansen,
Henrik B Rasmussen,
Jimmi Nielsen,
Gesche Jürgens,
Pierandrea Muglia,
Annette M Hartmann,
Eric Strengman, [......],
Michael J Owen,
Leena Peltonen,
Ole A Andreassen,
Markus M Nöthen,
David St Clair,
Roel A Ophoff,
Michael C O'Donovan,
David A Collier,
Thomas Werge,
Dan Rujescu
[show abstract]
[hide abstract]
ABSTRACT: The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18,920 controls. Both the replication study of new samples and the meta-analysis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P = 8.2 x 10(-5)-1.7 x 10(-3), common OR = 1.09-1.11). The region contains two genes, AHI1 and C6orf217, and both genes-as well as the neighbouring phosphodiesterase 7B (PDE7B)-may be considered candidates for involvement in the genetic aetiology of schizophrenia.
Human Molecular Genetics 04/2010; 19(7):1379-86. · 7.64 Impact Factor
