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Jurjen J Luykx,
Marco P M Boks,
Elemi J Breetvelt, Maartje F Aukes,
Eric Strengman,
Eleonora da Pozzo,
Annabel Vreeker,
Lucija Abramovic,
Claudia Martini,
Mattijs E Numans,
René S Kahn,
Roel A Ophoff
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ABSTRACT: A putative pathway by which the BDNF Val66Met polymorphism (rs6265) leads to aberrant phenotypes is its influence on plasma BDNF. Research into the impact of rs6265 on plasma BDNF has given rise to conflicting results. Moreover, most such studies have compared Met-carriers with Val-homozygous subjects. We therefore genotyped subjects from a population-based cohort (the Utrecht Health Project, N=2,743) and assessed whether plasma BDNF differs between rs6265 homozygous groups. We maximized the number of Met-homozygous subjects in whom we measured plasma BDNF, resulting in plasma BDNF being available for 19 Met-homozygous and 42 matched Val-homozygous subjects. Mean concentrations (S.D.) were 1963.1 (750.1) and 2133.2 pg/ml (1164.3) for the Val/Val and Met/Met groups, respectively. Using ANOVA, no differences in plasma BDNF between the two groups were detected. In conclusion, these results add to a growing body of evidence indicating that allelic variation at rs6265 does not have medium to large effects on plasma BDNF concentrations.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2012; · 3.25 Impact Factor
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ABSTRACT: Recent studies show that different aspects of smoking behavior are associated with the α-5 subunit of the nicotinic acetylcholine receptor (CHRNA5) gene and the gene coding for brain-derived neurotrophic factor (BDNF). This raises the question whether the amount of cigarettes smoked per day has a different genetic background than smoking initiation and what other smoking phenotypes may be relevant. The aim of this study was to replicate these associations in a large population-based sample. We investigated the association with smoking initiation and the number of cigarettes used per day and additional smoking phenotypes in a population-based sample of 2166 participants of Dutch origin. Rs6265 in BDNF was not associated with smoking initiation. This single nucleotide polymorphism was associated with smoking cessation. Rs16969968 in CHRNA5 was associated with the amount of nicotine used and in particular smoking 25 cigarettes or more per day. Overall, the results confirm the involvement of the CHRNA5 gene in the amount of nicotine use and further suggest involvement of the BDNF gene in smoking behavior.
Psychiatric genetics 04/2012; 22(2):96-8. · 2.33 Impact Factor
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ABSTRACT: To investigate familial clustering of schizophrenia, bipolar disorder, and major depressive disorder.
Combining data from a psychiatric case registry and Statistics Netherlands provided information on 4,673 affected probands and 18,692 matched population controls.
Probands with schizophrenia had relative risks (RRs) for having a sibling with schizophrenia of 3.77 (95% confidence interval (CI): 2.60-5.46) and with bipolar disorder of 1.79 (95% CI: 0.64-4.96) as compared with a reference proband. Probands affected with bipolar disorder have an RR of 6.51 (95% CI: 2.60-16.29) for having a sibling with bipolar disorder and of 1.71 (95% CI: 0.71-4.14) for having a sibling with schizophrenia as compared with a reference proband. Probands affected with major depressive disorder also have increased risk for having a sibling with schizophrenia (RR: 2.04, 95% CI: 1.54-2.72) as compared with a reference proband, which was similar to the risk for having a sibling with major depressive disorder (RR: 1.91, 95% CI: 1.63-2.24) or bipolar disorder (RR: 2.06, 95% CI: 1.18-3.60).
Our findings suggest, as previous studies have, that risk across schizophrenia and bipolar disorder is considerably lower (twofold) than within diagnostic entities, whereas for major depressive disorder risk is similar within and across diagnostic entities.
Genetics in medicine: official journal of the American College of Medical Genetics 03/2012; 14(3):338-41. · 3.92 Impact Factor
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ABSTRACT: We measured the association between paternal age and schizophrenia (SCZ), autism spectrum disorders (ASD), major depressive disorder (MDD), and bipolar disorder (BPD) in the Dutch population.
In total, 14231 patients and 56924 matched controls were collected and analyzed for an association with paternal age by logistic regression.
ASD is significantly associated with increased paternal age: Older fathers >40 years of age have a 3.3 times increased odds of having a child with ASD compared to young fathers <20 years of age. SCZ has significant associations for fathers aged >35 years (OR=1.27, 95% Confidence Interval: 1.05 and 1.53). For MDD, both younger and older fathers have increased odds. No association was found for BPD.
The effects of paternal age as a risk factor are different for ASD and SCZ on one hand, and the affective disorders on the other hand. Different types of association might indicate different biological or psychosocial mechanisms. Late paternity (associated with predispositions to psychiatric disorders) seems the most probable explanation for the association with paternal age.
Biological Psychiatry 07/2011; 129(2-3):128-32. · 8.28 Impact Factor
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ABSTRACT: A strategy to improve genetic studies of schizophrenia involves the use of endophenotypes. Information on overlapping genetic contributions among endophenotypes may provide additional power, reveal biological pathways, and have practical implications for genetic research. Several cognitive endophenotypes, including intelligence, are likely to be modulated by overlapping genetic influences.
We quantified potential genetic and environmental correlations among endophenotypes for schizophrenia, including sensorimotor gating, openness, verbal fluency, early visual perception, spatial working memory, and intelligence, using variance component models in 35 patients and 145 relatives from 25 multigenerational Dutch families multiply affected with schizophrenia.
Significant correlations were found between spatial working memory and intelligence (.45), verbal fluency and intelligence (.36), verbal fluency and spatial working memory (.20), and early visual perception and spatial working memory (.19). A strong genetic correlation (.75) accounted for 76% of the variance shared between spatial working memory and intelligence. Significant environmental correlations were found between verbal fluency and openness (.50) and between verbal fluency and spatial working memory (.58). Sensorimotor gating and openness showed few genetic or environmental correlations with other endophenotypes.
Our results suggest that intelligence strongly overlaps genetically with a known cognitive endophenotype for schizophrenia. Intelligence may thus be a promising endophenotype for genetic research in schizophrenia, even though the underlying genetic mechanism may still be complex. In contrast, sensorimotor gating and openness appear to represent separate genetic entities with simpler inheritance patterns and may therefore augment the detection of separate genetic pathways contributing to schizophrenia.
Biological psychiatry 12/2008; 65(6):527-34. · 8.93 Impact Factor
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ABSTRACT: Schizophrenia is a highly heritable and complex disorder. Multiple genes are likely to be involved, complicating genetic research into the etiology of this disorder. Intermediate phenotypes or endophenotypes may facilitate genetic research if they display a simpler mode of transmission than schizophrenia itself, i.e., if they reflect more closely the underlying genetic effects.
Twenty-five multigenerational families with multiple members affected with schizophrenia (180 subjects) were administered an extensive neuropsychological, psychophysiological, and personality test battery. Familial correlations were calculated to select heritable traits. Subsequent heritability analysis followed by commingling and segregation analysis were performed to unravel the pattern of transmission and to estimate heritability.
Five traits, including sensorimotor gating, openness, verbal fluency, early visual perception, and spatial working memory, showed moderate familial correlations. Heritability estimates for these traits ranged from 37% to 54%. A major gene model resembling dominant transmission was found for both sensorimotor gating and openness. Verbal fluency, early visual perception, and spatial working memory may be accounted for by polygenic, multifactorial, or environmental effects.
Only 2 of 13 candidate endophenotypes showed a simple mode of transmission useful for successful application in molecular genetic research: sensorimotor gating and openness. To our knowledge, this is the first study to investigate the pattern of transmission for these traits.
Biological psychiatry 08/2008; 64(2):128-36. · 8.93 Impact Factor
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ABSTRACT: The methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism has been associated with an increased risk of schizophrenia in various case-control studies. However, case-control studies are sensitive to population stratification, which is not an issue in family-based studies. We conducted a family-based study comprising 120 families with a schizophrenic family member to explore the association between the parental MTHFR 677C > T polymorphism and schizophrenia risk in offspring. In addition, a meta-analysis was performed using the available studies with data on this subject. Transmission Disequilibrium Test (TDT) analysis showed no preferential transmission of the 677T allele from parents heterozygous for the MTHFR 677C > T polymorphism to schizophrenia offspring (P = 0.27). The genotype relative risks were 1.43 (95% CI: 0.83–2.47) for the 677TT and 1.42 (95% CI: 0.54–3.78) for the 677CT genotype, relative to the 677CC genotype. A meta-analysis using data from family-based studies comprising a total of 416 parent-child triads yielded no evidence implicating the 677T allele in schizophrenia risk (P = 0.58). By applying a log-linear model, we found no asymmetry within parental mating type. Our data provided no evidence that transmission of the MTHFR 677T allele is associated with schizophrenia risk. In addition, we found no evidence that the maternal genotype influences the risk of having schizophrenia offspring substantially. © 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2007; 144B(7):891 - 894. · 3.70 Impact Factor
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ABSTRACT: The methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism has been associated with an increased risk of schizophrenia in various case-control studies. However, case-control studies are sensitive to population stratification, which is not an issue in family-based studies. We conducted a family-based study comprising 120 families with a schizophrenic family member to explore the association between the parental MTHFR 677C > T polymorphism and schizophrenia risk in offspring. In addition, a meta-analysis was performed using the available studies with data on this subject. Transmission Disequilibrium Test (TDT) analysis showed no preferential transmission of the 677T allele from parents heterozygous for the MTHFR 677C > T polymorphism to schizophrenia offspring (P = 0.27). The genotype relative risks were 1.43 (95% CI: 0.83-2.47) for the 677TT and 1.42 (95% CI: 0.54-3.78) for the 677CT genotype, relative to the 677CC genotype. A meta-analysis using data from family-based studies comprising a total of 416 parent-child triads yielded no evidence implicating the 677T allele in schizophrenia risk (P = 0.58). By applying a log-linear model, we found no asymmetry within parental mating type. Our data provided no evidence that transmission of the MTHFR 677T allele is associated with schizophrenia risk. In addition, we found no evidence that the maternal genotype influences the risk of having schizophrenia offspring substantially.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2007; 144B(7):891-4. · 3.70 Impact Factor
