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Article: Quantifying the Relative Importance of Genetics and Environment on the Comorbidity between Mental- and Cardiometabolic Disorders: A Comprehensive Analysis of National Register Data from 17 million Scandinavians.

Meijsen, Joeri / Hu, Kejia / Krebs, Morten Dybdahl / Athanasiadis, Georgios / Washbrook, Sarah / Zetterberg, Richard / E Silva, Raquel Nogueira Avelar / Shorter, John R / Gådin, Jesper R / Bergstedt, Jacob / Howard, David M / Ye, Weimin / Lu, Yi / Valdimarsdóttir, Unnur A / Ingason, Andrés / Mikkelsen, Dorte Helenius / Plana-Ripoll, Oleguer / McGrath, John J / Micali, Nadia /

Andreassen, Ole A / Werge, Thomas M / Fang, Fang / Buil, Alfonso

medRxiv : the preprint server for health sciences

2024

Abstract: Mental disorders (MDs) are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders (CMDs). Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records ... ...

Abstract	Mental disorders (MDs) are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders (CMDs). Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and complete genealogies of Denmark and Sweden (n=17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six MDs and 14 CMDs. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with CMDs, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with CMDs was mainly or fully driven by environmental factors. These findings provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.29.24303530
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Article ; Online: The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement.

Munch, Tina N / Hedley, Paula L / Hagen, Christian M / Bækvad-Hansen, Marie / Geller, Frank / Bybjerg-Grauholm, Jonas / Nordentoft, Merete / Børglum, Anders D / Werge, Thomas M / Melbye, Mads / Hougaard, David M / Larsen, Lars A / Christensen, Søren T / Christiansen, Michael

Brain communications

2023 Volume 5, Issue 1, Page(s) fcad004

Abstract: Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well ... ...

Abstract	Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well understood, but some association with dysfunctional cilia in the brain ventricles and subarachnoid space has been indicated. A better understanding of the genetic aetiology of hydrocephalus, including the role of ciliopathies, may bring insights into a potentially shared genetic aetiology. In this population-based case-cohort study, we, for the first time, investigated variants of postulated hydrocephalus candidate genes. Using these data, we aimed to investigate potential involvement of the ciliome in hydrocephalus and describe genotype-phenotype associations with an autism spectrum disorder. One-hundred and twenty-one hydrocephalus candidate genes were screened in a whole-exome-sequenced sub-cohort of the Lundbeck Foundation Initiative for Integrative Psychiatric Research study, comprising 72 hydrocephalus patients and 4181 background population controls. Candidate genes containing high-impact variants of interest were systematically evaluated for their involvement in ciliary function and an autism spectrum disorder. The median age at diagnosis for the hydrocephalus patients was 0 years (range 0-27 years), the median age at analysis was 22 years (11-35 years), and 70.5% were males. The median age for controls was 18 years (range 11-26 years) and 53.3% were males. Fifty-two putative hydrocephalus-associated variants in 34 genes were identified in 42 patients (58.3%). In hydrocephalus cases, we found increased, but not significant, enrichment of high-impact protein altering variants (odds ratio 1.51, 95% confidence interval 0.92-2.51,
Language	English
Publishing date	2023-01-10
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcad004
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Article ; Online: Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control.

Maurer, Gianna W / Malita, Alina / Nagy, Stanislav / Koyama, Takashi / Werge, Thomas M / Halberg, Kenneth A / Texada, Michael J / Rewitz, Kim

PLoS genetics

2020 Volume 16, Issue 4, Page(s) e1008727

Abstract: The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of known genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. ... ...

Abstract	The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of known genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. To investigate the effect of individual genes within this interval on the pathophysiology associated with the deletion, we analyzed their role in sleep, a behavior affected in virtually all psychiatric disorders, including the 22q11.2 DS. We identified the gene LZTR1 (night owl, nowl) as a regulator of night-time sleep in Drosophila. In humans, LZTR1 has been associated with Ras-dependent neurological diseases also caused by Neurofibromin-1 (Nf1) deficiency. We show that Nf1 loss leads to a night-time sleep phenotype nearly identical to that of nowl loss and that nowl negatively regulates Ras and interacts with Nf1 in sleep regulation. Furthermore, nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl regulates sleep through modulation of GABA signaling. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling important for normal sleep that contributes to the 22q11.2 DS.
MeSH term(s)	22q11 Deletion Syndrome/genetics ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Drosophila ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; GABAergic Neurons/metabolism ; GABAergic Neurons/physiology ; Humans ; Neurofibromin 1/genetics ; Neurofibromin 1/metabolism ; Receptors, GABA-A/metabolism ; Schizophrenia/genetics ; Sleep/genetics ; Transcription Factors/genetics
Chemical Substances	Adaptor Proteins, Signal Transducing ; Drosophila Proteins ; LZTR1 protein, human ; Lztr1 protein, Drosophila ; Neurofibromin 1 ; Receptors, GABA-A ; Transcription Factors
Language	English
Publishing date	2020-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1008727
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Article ; Online: AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance.

Nagy, Stanislav / Maurer, Gianna W / Hentze, Julie L / Rose, Morten / Werge, Thomas M / Rewitz, Kim

PLoS genetics

2018 Volume 14, Issue 12, Page(s) e1007623

Abstract: The human 1q21.1 deletion of ten genes is associated with increased risk of schizophrenia. This deletion involves the β-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for ... ...

Abstract	The human 1q21.1 deletion of ten genes is associated with increased risk of schizophrenia. This deletion involves the β-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for energy and low capacity to store nutrients, the role of AMPK in neuronal physiology is poorly defined. Here we show that AMPK is important in the nervous system for maintaining neuronal integrity and for stress survival and longevity in Drosophila. To understand the impact of this signaling system on behavior and its potential contribution to the 1q21.1 deletion syndrome, we focused on sleep, an important role of which is proposed to be the reestablishment of neuronal energy levels that are diminished during energy-demanding wakefulness. Sleep disturbances are one of the most common problems affecting individuals with psychiatric disorders. We show that AMPK is required for maintenance of proper sleep architecture and for sleep recovery following sleep deprivation. Neuronal AMPKβ loss specifically leads to sleep fragmentation and causes dysregulation of genes believed to play a role in sleep homeostasis. Our data also suggest that AMPKβ loss may contribute to the increased risk of developing mental disorders and sleep disturbances associated with the human 1q21.1 deletion.
MeSH term(s)	AMP-Activated Protein Kinases/antagonists & inhibitors ; AMP-Activated Protein Kinases/deficiency ; AMP-Activated Protein Kinases/genetics ; Abnormalities, Multiple/enzymology ; Abnormalities, Multiple/genetics ; Animals ; Chromosome Deletion ; Chromosomes, Human, Pair 1/enzymology ; Chromosomes, Human, Pair 1/genetics ; Drosophila Proteins/deficiency ; Drosophila Proteins/genetics ; Drosophila melanogaster/enzymology ; Drosophila melanogaster/genetics ; Female ; Gene Knockdown Techniques ; Genetic Predisposition to Disease ; Humans ; Learning/physiology ; Longevity/genetics ; Longevity/physiology ; Male ; Megalencephaly/enzymology ; Megalencephaly/genetics ; Models, Animal ; Neurons/cytology ; Neurons/enzymology ; Risk Factors ; Schizophrenia/enzymology ; Schizophrenia/genetics ; Signal Transduction ; Sleep/genetics ; Sleep/physiology ; Sleep Wake Disorders/enzymology ; Sleep Wake Disorders/genetics
Chemical Substances	Drosophila Proteins ; PRKAB2 protein, human (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2018-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1007623
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Article ; Online: Interactive effects between hemizygous 15q13.3 microdeletion and peripubertal stress on adult behavioral functions.

Giovanoli, Sandra / Werge, Thomas M / Mortensen, Preben B / Didriksen, Michael / Meyer, Urs

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2018 Volume 44, Issue 4, Page(s) 703–710

Abstract: 15q13.3 microdeletion is one of several gene copy number variants (CNVs) conferring increased risk of psychiatric and neurological disorders. This microdeletion gives rise to a variable spectrum of pathological phenotypes, ranging from asymptomatic to ... ...

Abstract	15q13.3 microdeletion is one of several gene copy number variants (CNVs) conferring increased risk of psychiatric and neurological disorders. This microdeletion gives rise to a variable spectrum of pathological phenotypes, ranging from asymptomatic to severe clinical outcomes. The reasons for these varying phenotypic outcomes remain unknown. Using a mouse model of hemizygous deletion of the orthologous region of 15q13.3, the present study examined whether exposure to stressful life events might interact with hemizygous 15q13.3 microdeletion in the development of behavioral dysfunctions. We show that hemizygous 15q13.3 microdeletion alone induces only limited effects on adult behaviors, but when combined with psychological stress in pubescence (postnatal days 30-40), it impairs sensorimotor gating and increases the sensitivity to the psychostimulant drug, amphetamine, at adult age. Stress exposure in adolescence (postnatal days 50-60) did not induce similar interactions with 15q13.3 microdeletion, but led to impaired emotional learning and memory and social behavior regardless of the genetic background. The present study provides the first evidence for interactive effects between hemizygous 15q13.3 microdeletion and exposure to stressful life events, and at the same time, it emphasizes an important influence of the precise timing of postnatal stress exposure in these interactions. Our findings suggest that hemizygous 15q13.3 microdeletion can act as a "disease primer" that increases the carrier's vulnerability to the detrimental effects of peripubertal stress exposure on adult behaviors.
MeSH term(s)	Age Factors ; Amphetamine/pharmacology ; Anhedonia/physiology ; Animals ; Anxiety/physiopathology ; Behavior, Animal/physiology ; Central Nervous System Stimulants/pharmacology ; Chromosome Deletion ; Chromosome Disorders/complications ; Chromosome Disorders/physiopathology ; Chromosomes, Human, Pair 15 ; Disease Models, Animal ; Emotions/physiology ; Hemizygote ; Intellectual Disability/complications ; Intellectual Disability/physiopathology ; Learning/physiology ; Mice ; Mice, Inbred C57BL ; Seizures/complications ; Seizures/physiopathology ; Sensory Gating/drug effects ; Sensory Gating/physiology ; Sexual Maturation/physiology ; Social Behavior ; Stress, Psychological/physiopathology
Chemical Substances	Central Nervous System Stimulants ; Amphetamine (CK833KGX7E)
Language	English
Publishing date	2018-08-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-018-0189-3
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Zs.A 2379: Show issues

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Article: Novel procedure for genotyping of the human serotonin transporter gene-linked polymorphic region (5-HTTLPR)--a region with a high level of allele diversity.

Rasmussen, Henrik B / Werge, Thomas M

Psychiatric genetics

2007 Volume 17, Issue 5, Page(s) 287–291

Abstract: Background: The serotonin transporter, the target of a group of antidepressant drugs, is involved in the regulation of the availability and reuptake of serotonin. A variable number of tandem repeats in the promoter region of the serotonin transporter ... ...

Abstract	Background: The serotonin transporter, the target of a group of antidepressant drugs, is involved in the regulation of the availability and reuptake of serotonin. A variable number of tandem repeats in the promoter region of the serotonin transporter gene, designated 5-HTTLPR, affects the transcription of this gene and appears to modulate the susceptibility to a variety of diseases including depression. Of importance, 5-HTTLPR alleles composed of the same number of basic units may differ at single nucleotide positions providing an additional source of variation. Objective: To develop a procedure for detailed genotyping of 5-HTTLPR based upon simultaneous analysis of tandem repeat size variation and single nucleotide variations. Methods: We elaborated a list of all known 5-HTTLPR alleles to provide an overview of the allele repertoire at this polymorphic locus. Fragments of 5-HTTLPR were PCR-amplified in reaction mixtures prepared with and without 7-deaza-dGTP. The amplified fragments were treated with NciI and NlaIII and subjected to agarose gel electrophoresis. Alleles were identified by comparison of the observed electrophoretic patterns with the predicted patterns. Two hundred samples of human genomic DNA representing a variety of different 5-HTTLPR alleles were included in the study. Main results: We were able to amplify fragments of 5-HTTLPR, which are GC-rich, without the use of 7-deaza-dGTP. This is an advantage as modified nucleotides may inhibit restriction enzymes and interfere with allele determination. After having developed a 5-HTTLPR genotyping assay, we examined all samples of DNA in two separate rounds of analyses and found complete agreement between the results from these two rounds. Conclusion: On the basis of simultaneous analysis of tandem repeat size variation and variation of single nucleotides we designed a reliable assay for the determination of the major alleles and several of the rare alleles at the polymorphic locus 5-HTTLPR.
MeSH term(s)	DNA/blood ; DNA/genetics ; DNA/isolation & purification ; Genetic Variation ; Genotype ; Humans ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Restriction Mapping ; Serotonin Plasma Membrane Transport Proteins/genetics
Chemical Substances	SLC6A4 protein, human ; Serotonin Plasma Membrane Transport Proteins ; DNA (9007-49-2)
Language	English
Publishing date	2007-10
Publishing country	England
Document type	Journal Article
ZDB-ID	1067837-2
ISSN	1473-5873 ; 0955-8829
ISSN (online)	1473-5873
ISSN	0955-8829
DOI	10.1097/YPG.0b013e328133f331
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Zs.A 3165: Show issues

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Article ; Online: Genetic regulation of spermine oxidase activity and cancer risk: a Mendelian randomization study.

Fadista, João / Yakimov, Victor / Võsa, Urmo / Hansen, Christine S / Kasela, Silva / Skotte, Line / Geller, Frank / Courraud, Julie / Esko, Tõnu / Kukuškina, Viktorija / Buil, Alfonso / Melbye, Mads / Werge, Thomas M / Hougaard, David M / Milani, Lili / Bybjerg-Grauholm, Jonas / Cohen, Arieh S / Feenstra, Bjarke

Scientific reports

2021 Volume 11, Issue 1, Page(s) 17463

Abstract: Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. ... ...

Abstract	Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 × 10
MeSH term(s)	Adult ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Humans ; Infant, Newborn ; Mendelian Randomization Analysis/methods ; Neoplasms/etiology ; Neoplasms/metabolism ; Neoplasms/pathology ; Oxidoreductases Acting on CH-NH Group Donors/genetics ; Phenotype ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Polyamine Oxidase
Chemical Substances	Oxidoreductases Acting on CH-NH Group Donors (EC 1.5.-)
Language	English
Publishing date	2021-08-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-97069-x
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Article ; Online: Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder.

LaBianca, Sonja / Brikell, Isabell / Helenius, Dorte / Loughnan, Robert / Mefford, Joel / Palmer, Clare E / Walker, Rebecca / Gådin, Jesper R / Krebs, Morten / Appadurai, Vivek / Vaez, Morteza / Agerbo, Esben / Pedersen, Marianne Giørtz / Børglum, Anders D / Hougaard, David M / Mors, Ole / Nordentoft, Merete / Mortensen, Preben Bo / Kendler, Kenneth S /

Jernigan, Terry L / Geschwind, Daniel H / Ingason, Andrés / Dahl, Andrew W / Zaitlen, Noah / Dalsgaard, Søren / Werge, Thomas M / Schork, Andrew J

Nature genetics

2023 Volume 56, Issue 2, Page(s) 234–244

Abstract: Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links ...

Abstract	Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links to clinical heterogeneity in ADHD in a case-only study of 14,084 diagnosed individuals. First, we identify one genome-wide significant locus by comparing cases with ADHD and autism spectrum disorder (ASD) to cases with ADHD but not ASD. Second, we show that cases with ASD and ADHD, substance use disorder and ADHD, or first diagnosed with ADHD in adulthood have unique polygenic score (PGS) profiles that distinguish them from complementary case subgroups and controls. Finally, a PGS for an ASD diagnosis in ADHD cases predicted cognitive performance in an independent developmental cohort. Our approach uncovered evidence of genetic heterogeneity in ADHD, helping us to understand its etiology and providing a model for studies of other disorders.
MeSH term(s)	Humans ; Autism Spectrum Disorder/genetics ; Attention Deficit Disorder with Hyperactivity/genetics ; Multifactorial Inheritance/genetics
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01593-7
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility? Analysis of Data From the Nationwide Danish Twin Register.

Hilker, Rikke / Helenius, Dorte / Fagerlund, Birgitte / Skytthe, Axel / Christensen, Kaare / Werge, Thomas M / Nordentoft, Merete / Glenthøj, Birte

EBioMedicine

2017 Volume 18, Page(s) 320–326

Abstract: Background: Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of ... ...

Abstract	Background: Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals with a shared genetic background. Methods: We linked nationwide registers to identify a cohort of twin pairs born in Denmark from 1951 to 2000 (N=31,524 pairs), where one or both twins had a diagnosis in the schizophrenia spectrum. We defined two groups consisting of; N=788 twin pairs (affected with schizophrenia spectrum) and a subsample of N=448 (affected with schizophrenia). Survival analysis was applied to investigate the effect of age at illness onset. Findings: We found that early age at illness onset compared to later onset in the first diagnosed twin can be considered a major risk factor for developing schizophrenia in the second twin. Additionally, we found that the stronger genetic component in MZ twins compared to DZ twins is manifested in the proximity of assigned diagnosis within pairs. Discussion: Early onset schizophrenia could be linked to a more severe genetic predisposition, indicating that age might be perceived as a clinical marker for genetic vulnerability for the illness.
Language	English
Publishing date	2017-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2017.04.002
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Zs.A 7090: Show issues

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Article ; Online: Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register.

Hilker, Rikke / Helenius, Dorte / Fagerlund, Birgitte / Skytthe, Axel / Christensen, Kaare / Werge, Thomas M / Nordentoft, Merete / Glenthøj, Birte

Biological psychiatry

2017 Volume 83, Issue 6, Page(s) 492–498

Abstract: Background: Twin studies have provided evidence that both genetic and environmental factors contribute to schizophrenia (SZ) risk. Heritability estimates of SZ in twin samples have varied methodologically. This study provides updated heritability ... ...

Abstract	Background: Twin studies have provided evidence that both genetic and environmental factors contribute to schizophrenia (SZ) risk. Heritability estimates of SZ in twin samples have varied methodologically. This study provides updated heritability estimates based on nationwide twin data and an improved statistical methodology. Methods: Combining two nationwide registers, the Danish Twin Register and the Danish Psychiatric Research Register, we identified a sample of twins born between 1951 and 2000 (N = 31,524 twin pairs). Twins were followed until June 1, 2011. Liability threshold models adjusting for censoring with inverse probability weighting were used to estimate probandwise concordance rates and heritability of the diagnoses of SZ and SZ spectrum disorders. Results: The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. We estimated the heritability of SZ to be 79%. When expanding illness outcome to include SZ spectrum disorders, the heritability estimate was almost similar (73%). Conclusions: The key strength of this study is the application of a novel statistical method accounting for censoring in the follow-up period to a nationwide twin sample. The estimated 79% heritability of SZ is congruent with previous reports and indicates a substantial genetic risk. The high genetic risk also applies to a broader phenotype of SZ spectrum disorders. The low concordance rate of 33% in monozygotic twins demonstrates that illness vulnerability is not solely indicated by genetic factors.
MeSH term(s)	Adult ; Denmark/epidemiology ; Diseases in Twins ; Female ; Gene-Environment Interaction ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Registries ; Risk Factors ; Schizophrenia/epidemiology ; Schizophrenia/genetics ; Surveys and Questionnaires ; Twins, Dizygotic ; Twins, Monozygotic ; Young Adult
Language	English
Publishing date	2017-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Twin Study
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2017.08.017
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