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Evangelos Vassos,
Stacy Steinberg,
Sven Cichon,
Gerome Breen, Engilbert Sigurdsson,
Ole A Andreassen,
Srdjan Djurovic,
Gunnar Morken,
Maria Grigoroiu-Serbanescu,
Carmen C Diaconu, [......],
I Alex Rubino,
Vera Golimbet,
Lambertus A Kiemeney,
Leonard H van den Berg,
Barbara Franke,
Erik G Jönsson,
Anne Farmer,
Hreinn Stefansson,
Kari Stefansson,
David A Collier
[show abstract]
[hide abstract]
ABSTRACT: Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia.
To replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method.
In our dataset, rs2251219 was associated with BP (odds ratio [OR] = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 × 10(-9)). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21).
There is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder.
Biological psychiatry 05/2012; 72(8):645-50. · 8.93 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: BackgroundDeficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes in genetic studies of schizophrenia.
The Icelandic population lends itself ideally to genetic studies due to its ethnic homogeneity and well-documented genealogy.
The primary aim of this study was to assess AS and SPEM performance in a large Icelandic sample. Additional aims were to investigate
the relationship between AS and SPEM task performance and to assess internal consistency, within-session performance changes
and effects of SPEM target velocity on performance.
MethodPatients with schizophrenia (N=118) and healthy controls (N=109) matched for age and gender underwent infrared oculographic assessment of AS and SPEM (at target velocities of 12°,
24° and 36°/s).
ResultsOn the AS task patients displayed significantly more reflexive errors, longer latency, increased intra-individual latency
variability, and reduced amplitude gain compared to controls. On the SPEM task, patients had significantly lower velocity
gain and more frequent saccades during pursuit at all velocities, but group differences in velocity gain increased with increasing
target velocity. Internal consistency of performance was high for all variables in both groups (Cronbach’s alpha>0.77 for
AS and >0.85 for SPEM) except for AS spatial error in patients (alpha=0.38). A moderate association was found between AS
and SPEM performance. By and large, patients and controls showed similar patterns of systematic within-session performance
changes.
ConclusionsOur findings confirm the existence of robust eye movement deficits in schizophrenia in a large sample. These measures may
be studied as endophenotypes in future studies of potential schizophrenia risk genotypes in the genetically homogenous Icelandic
population.
European Archives of Psychiatry and Clinical Neuroscience 04/2012; 258(6):373-383. · 3.49 Impact Factor
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Yongyong Shi,
Zhiqiang Li,
Qi Xu,
Ti Wang,
Tao Li,
Jiawei Shen,
Fengyu Zhang,
Jianhua Chen,
Guoquan Zhou,
Weidong Ji, [......],
David St Clair,
Hreinn Stefansson,
Kari Stefansson,
Jue Ji,
Qingzhong Wang,
Wenjin Li,
Linqing Zheng,
Hairong Zhang,
Guoyin Feng,
Lin He
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia is a severe mental disorder affecting ∼1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10(-10)) and 1q24.2 (rs10489202, P = 9.50 × 10(-9)). Our findings provide new insights into the pathogenesis of schizophrenia.
Nature Genetics 12/2011; 43(12):1224-7. · 35.53 Impact Factor
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Noa Carrera,
Manuel Arrojo,
Julio Sanjuán,
Ramón Ramos-Ríos,
Eduardo Paz,
Jose J Suárez-Rama,
Mario Páramo,
Santiago Agra,
Julio Brenlla,
Silvia Martínez, [......],
Thomas Werge,
Kari Stefansson,
Jose Carlos González,
Joaquín Valero,
Alfonso Gutiérrez-Zotes,
Antonio Labad,
Lourdes Martorell,
Elisabet Vilella,
Ángel Carracedo,
Javier Costas
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs).
We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures.
The 5 independent nsSNPs with false discovery rate q ≤ .25, as well as 13 additional nsSNPs at p < .01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10(-6), allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility.
Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.
Biological psychiatry 11/2011; 71(2):169-77. · 8.93 Impact Factor
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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
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Engilbert Sigurdsson
Laeknabladid 09/2011; 97(9):461. · 0.23 Impact Factor
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Sébastien Jacquemont,
Alexandre Reymond,
Flore Zufferey,
Louise Harewood,
Robin G Walters,
Zoltán Kutalik,
Danielle Martinet,
Yiping Shen,
Armand Valsesia,
Noam D Beckmann, [......],
Joris Andrieux,
Xavier Estivill,
James F Gusella,
Omar Gustafsson,
Andres Metspalu,
Stephen W Scherer,
Kari Stefansson,
Alexandra I F Blakemore,
Jacques S Beckmann,
Philippe Froguel
[show abstract]
[hide abstract]
ABSTRACT: Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.
Nature 08/2011; 478(7367):97-102. · 36.28 Impact Factor
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Stacy Steinberg,
Simone de Jong,
Ole A Andreassen,
Thomas Werge,
Anders D Børglum,
Ole Mors,
Preben B Mortensen,
Omar Gustafsson,
Javier Costas,
Olli P H Pietiläinen, [......],
Sarah Tosato,
Leena Peltonen,
Roel A Ophoff,
David A Collier,
David St Clair,
Marcella Rietschel,
Sven Cichon,
Hreinn Stefansson,
Dan Rujescu,
Kari Stefansson
[show abstract]
[hide abstract]
ABSTRACT: 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)).
Human Molecular Genetics 08/2011; 20(20):4076-81. · 7.64 Impact Factor
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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
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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
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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
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Sven Cichon,
Thomas W Mühleisen,
Franziska A Degenhardt,
Manuel Mattheisen,
Xavier Miró,
Jana Strohmaier,
Michael Steffens,
Christian Meesters,
Stefan Herms,
Moritz Weingarten, [......],
Joanna Hauser,
Andreas Zimmer,
Mark Lathrop,
Thomas G Schulze,
Thomas F Wienker,
Johannes Schumacher,
Wolfgang Maier,
Peter Propping,
Marcella Rietschel,
Markus M Nöthen
[show abstract]
[hide abstract]
ABSTRACT: We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.
The American Journal of Human Genetics 02/2011; 88(3):372-81. · 10.60 Impact Factor
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Engilbert Sigurdsson
Laeknabladid 01/2011; 97(1):7. · 0.23 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: There is strong evidence for significant contributions of genetic factors to the risk of schizophrenia. In the past 10 years, studies employing linkage and association approaches have identified multiple putative schizophrenia risk genes. For most of these, the evidence for association with schizophrenia remains weak and attempts of replication not always successful nor easy to interpret.
To give an overview of new developments in genetic research of schizophrenia.
The present literature on schizophrenia genetics was reviewed with special emphasis on new developments such as genome-wide association studies (GWAS), associations of copy number variations (CNVs) with schizophrenia and the role of endophenotypes in genetic research.
The first GWAS of schizophrenia have identified new putative candidate risk genes and opened avenues for investigating how multiple genes may act in functional biological pathways forming the genetic basis of schizophrenia and other complex diseases. There is growing evidence that rare de novo CNVs as well as some inherited CNVs contribute to the susceptibility to several neuropsychiatric disorders including schizophrenia. Schizophrenia endophenotypes, which possibly better represent biological phenomena than the complex clinical phenotype, are turning out to be helpful for investigating neurobiological pathways of putative risk genes.
Recent studies suggest that individual common gene variants make relatively small contributions to risk of schizophrenia but some rare CNVs may be associated with much higher risk when present. Future studies employing new technologies for identifying common and rare risk markers are likely to deepen our understanding of the genetic architecture of schizophrenia.
Nordic journal of psychiatry 01/2011; 65(2):82-8. · 0.99 Impact Factor
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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
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Lavinia Athanasiu,
Morten Mattingsdal,
Anna K Kähler,
Andrew Brown,
Omar Gustafsson,
Ingrid Agartz,
Ina Giegling,
Pierandrea Muglia,
Sven Cichon,
Marcella Rietschel, [......],
Elvira Bramon,
David Collier,
David St Clair, Engilbert Sigurdsson,
Hannes Petursson,
Dan Rujescu,
Ingrid Melle,
Vidar M Steen,
Srdjan Djurovic,
Ole A Andreassen
[show abstract]
[hide abstract]
ABSTRACT: We have performed a genome-wide association study (GWAS) of schizophrenia in a Norwegian discovery sample of 201 cases and 305 controls (TOP study) with a focused replication analysis in a larger European sample of 2663 cases and 13,780 control subjects (SGENE-plus study). Firstly, the discovery sample was genotyped with Affymetrix Genome-Wide Human SNP Array 6.0 and 572,888 markers were tested for schizophrenia association. No SNPs in the discovery sample attained genome-wide significance (P<8.7 x 10(-8)). Secondly, based on the GWAS data, we selected 1000 markers with the lowest P values in the discovery TOP sample, and tested these (or HapMap-based surrogates) for association in the replication sample. Sixteen loci were associated with schizophrenia (nominal P value<0.05 and concurring OR) in the replication sample. As a next step, we performed a combined analysis of the findings from these two studies, and the strongest evidence for association with schizophrenia was provided for markers rs7045881 on 9p21, rs433598 on 16p12 and rs10761482 on 10q21. The markers are located in PLAA, ACSM1 and ANK3, respectively. PLAA has not previously been described as a susceptibility gene, but 9p21 is implied as a schizophrenia linkage region. ACSM1 has been identified as a susceptibility gene in a previous schizophrenia GWAS study. The association of ANK3 with schizophrenia is intriguing in light of recent associations of ANK3 with bipolar disorder, thereby supporting the hypothesis of an overlap in genetic susceptibility between these psychopathological entities.
Journal of psychiatric research 02/2010; 44(12):748-53. · 3.72 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Exposure to high altitude can lead to acute mountain sickness (AMS) and high altitude cerebral edema (HACE). In this study we investigated the effect of high altitude on neurocognitive function and S100B release. Increased S100B release has been hypothesized to signify a loss of integrity in the blood-brain barrier (BBB). Seven healthy volunteers trekked to Capanna Regina Margherita (4554 m above sea level) in the Monte Rosa massif. During ascent and descent, five test events were undertaken; participants underwent neurocognitive testing, Lake Louise scoring (LLS), and blood sampling to measure levels of S100B. The blood tests revealed that S100B levels increased 42% to 122% from baseline, and mean LLS increased from 0.57 to 2.57. A significant correlation was observed between both S100B levels and LLS and S100B and some neurocognitive scores. The study indicates that S100B can be released by a mild hypoxia during AMS. Moreover, an observed correlation between S100B and a lower score on neurocognitive tests suggests that the pathogenetic mechanisms may be linked. The study indicates that a decline in cognitive function is associated with symptoms of AMS.
High altitude medicine & biology 01/2010; 11(1):31-8. · 1.58 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: In the past 5 years the Icelandic Medical Journal has undergone many changes during a period of flourishing research in Iceland. The process of reviewing and editing scientific articles has been revised since the Journal joined the Medline database in 2005 and the proportion of rejected articles has risen. New columns have been launched covering medical history, professionalism, ethics and hobbies of the medical profession.
We categorized all scientific articles from the period 2004-2008, that is research articles, review articles, case reports and clinical guidelines, according to types of articles and to which medical speciality or subspeciality the publication should belong.
The number of scientific articles rose during the period but the number of research articles remained around 20 most years during the period. The relative proportion of research articles therefore fell whereas the number and proportion of review articles and case reports increased. Clinical guidelines ceased to appear in the Journal. The contribution of individual specialities to the Journal varied widely.
Researchers amongst doctors and related professions need be encouraged to submit scientific articles to the Journal. The publication of scientific articles in English in the web-based form of the Journal may prove to be stimulating in this regard for Icelandic doctors abroad as well as for some researchers in Iceland.
Laeknabladid 10/2009; 95(10):683-6. · 0.23 Impact Factor
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Hreinn Stefansson,
Roel A Ophoff,
Stacy Steinberg,
Ole A Andreassen,
Sven Cichon,
Dan Rujescu,
Thomas Werge,
Olli P H Pietiläinen,
Ole Mors,
Preben B Mortensen, [......],
Hannes Petursson,
Markus M Nöthen,
Marcella Rietschel,
Paul M Matthews,
Pierandrea Muglia,
Leena Peltonen,
David St Clair,
David B Goldstein,
Kari Stefansson,
David A Collier
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ABSTRACT: 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.
Nature 08/2009; 460(7256):744-7. · 36.28 Impact Factor
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ABSTRACT: Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain dysfunctions underlying the pathophysiology of schizophrenia. The aim of this study was to investigate the associations of NRG-1 genotypes with AS and SPEM in schizophrenia patients and healthy controls. Patients (N = 113) and controls (N = 106) were genotyped for two NRG-1 single nucleotide polymorphisms (SNPs); SNP8NRG222662, a surrogate marker for the originally described Icelandic NRG-1 risk haplotype, and SNP8NRG243177, which has recently been associated with individual differences in brain function. Subjects underwent infrared oculographic assessment of AS and SPEM. The study replicates previous findings of impaired AS and SPEM performance in schizophrenia patients (all P < 0.005; all d = 0.5-1.5). SNP8NRG243177 risk allele carriers had marginally increased variability of AS spatial error (P = 0.050, d = 0.3), but there were no significant genotype effects on other eye movement variables and no significant diagnosis-by-genotype interactions. Generally, risk allele carriers (G allele for SNP8NRG222662 and T allele for SNP8NRG243177) had numerically worse performance than non-carriers on most AS and SPEM variables. The results do not suggest that NRG-1 genotype significantly affects AS and SPEM task performance. However, the power of the sample to identify small effects is limited and the possibility of a type II error must be kept in mind. Larger samples may be needed to reliably investigate such gene effects on oculomotor endophenotypes.
Archiv f ur Psychiatrie und Nervenkrankheiten 08/2009; 260(1):77-85. · 2.75 Impact Factor
