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ABSTRACT: Context and Objective: Information on the correlation of normative reproductive hormone levels with physical development (Tanner stages) during puberty and on the influences of genes and environment on variation in these hormones and Tanner stages is limited. Design, Setting, and Participants: One hundred twelve healthy 9-year-old twin pairs (n = 224) took part in a longitudinal study, of which 89 pairs participated again at age 12 years (n = 178). Main Outcome Measures: Morning urinary LH, FSH, estradiol, and salivary testosterone levels, determined by competitive immunoassays, were measured. Tanner stages were determined through physical examination. Results: Over the 3-year interval, all hormone levels showed a 2- to 9-fold increase. LH and FSH at age 9 years predicted sex-specific Tanner stages at age 12 years in both boys and girls. Most of the associations between hormone levels at age 9 years and physical development at 12 years were explained by genetic influences. FSH in 9-year-old boys correlated with all hormone levels and Tanner stages at age 12 years. Moderate to high heritability estimates were found for hormone levels at both ages and in both sexes. In girls a shift from environmental (age 9 years) to genetic influences (age 12 years) was found for estradiol and pubic hair development, and for breast development a shift in the opposite direction was seen. Conclusions: During development LH and FSH (and testosterone in boys) levels predict secondary sexual characteristics in boys and girls 3 years later. These correlations are largely due to genes that are involved in both early pubertal hormone levels and subsequent physical development.
The Journal of clinical endocrinology and metabolism 03/2013; 98(3):E518-27. · 6.50 Impact Factor
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ABSTRACT: AIMS/HYPOTHESIS: We examined the effects of serum insulin levels on vagal control over the heart and tested the hypothesis that higher fasting insulin levels are associated with lower vagal control. We also examined whether experimentally induced increases in insulin by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine). RESULTS: Serum insulin level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp. Insulin levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log(10)HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine). These associations disappeared when adjusted for age, BMI and insulin sensitivity. Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and insulin sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control.
Diabetologia 02/2013; · 6.81 Impact Factor
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B Benyamin,
Bst Pourcain,
O S Davis,
G Davies,
N K Hansell,
M-Ja Brion,
R M Kirkpatrick,
R A M Cents,
S Franić,
M B Miller, [......],
G W Montgomery,
N G Martin, D I Boomsma,
D Posthuma,
M McGue,
M J Wright,
G Davey Smith,
I J Deary,
R Plomin,
P M Visscher
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ABSTRACT: Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.Molecular Psychiatry advance online publication, 29 January 2013; doi:10.1038/mp.2012.184.
Molecular psychiatry 01/2013; · 15.05 Impact Factor
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ABSTRACT: Het Composite International Diagnostic Interview (cidi; World Health Organization, 1992a) is een volledig gestructureerd interview, dat is ontwikkeld door de World Health Organisation
(who) om psychiatrische diagnosen te stellen volgens de criteria van de Diagnostic and statistical manual of mental disorders (dsm; American Psychiatric Association, 1987, 1994) of de International classification of diseases (icd; World Health Organization, 1992b).
Netherlands journal of psychology 04/2012; 61(2):123-126.
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D H van Raalte,
N van Leeuwen,
A M Simonis-Bik,
G Nijpels,
T W van Haeften,
S A Schafer, D I Boomsma,
M H H Kramer,
R J Heine,
J A Maassen, [......],
F Machicao,
H-U Häring,
P E Slagboom,
G Willemsen,
E J de Geus,
J M Dekker,
A Fritsche,
E M Eekhoff,
M Diamant,
L M 't Hart
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ABSTRACT: Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting β-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of β-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance.
A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance (n=261) and impaired glucose tolerance (n=188). From 2-h hyperglycaemic clamps, first- and second-phase glucose-stimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/6190), 9β A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and β-cell function parameters were assessed.
In women, but not in men, the N363S polymorphism was associated with reduced disposition index (P=1.06 10(-4) ). Also only in women, the ER22/23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion (P=0.011) and disposition index (P=0.003). The other single-nucleotide polymorphisms were not associated with β-cell function. Finally, none of the polymorphisms was related to insulin sensitivity.
The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of β-cell function in women, but not in men.
Diabetic Medicine 04/2012; 29(8):e211-6. · 2.90 Impact Factor
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P H Lee,
R H Perlis,
J-Y Jung,
E M Byrne,
E Rueckert,
R Siburian,
S Haddad,
C E Mayerfeld,
A C Heath,
M L Pergadia,
P A F Madden, D I Boomsma,
B W Penninx,
P Sklar,
N G Martin,
N R Wray,
S M Purcell,
J W Smoller
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ABSTRACT: Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P=6.9 × 10(-4)). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD.
Translational psychiatry. 01/2012; 2:e184.
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ABSTRACT: Triplets often have a low birth weight. This is partly due to low gestational age; they are often born premature. However, zygosity and chorionicity also affect birth weight. Triplets, which refers to one child (the set of three triplets is referred to as a 'trio'), can be either monochorionic (MC), dichorionic (DC) or trichorionic (TC). A smaller number of chorions is associated with lower birth weight because sharing a placenta causes competition for nutrients (Adegbite, Ward, & Bajoria, 2005; Bajoria, Ward, & Adegbite, 2006; Geipel et al., 2005). In addition, there is some evidence that when more triplets share a chorion the gestational age of the trio is lower (Spencer et al., 2009). Zygosity also is an important factor in birth weight, but is not independent from chorionicity. Monozygotic (MZ) triplets can share one chorion, can be DC, or have each their own chorion (i.e. trichorionic, TC); dizygotic (DZ) triplets are DC or TC; trizygotic (TZ) triplets are always RECEIVED 24 December, 2011; ACCEPTED 10 January, 2012.
Twin Research and Human Genetics 01/2012; 15(10-2):149--157. · 1.70 Impact Factor
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ABSTRACT: During development from childhood to adulthood the human brain undergoes considerable thinning of the cerebral cortex. Whether developmental cortical thinning is influenced by genes and if independent genetic factors influence different parts of the cortex is not known. Magnetic resonance brain imaging was done in twins at age 9 (N = 190) and again at age 12 (N = 125; 113 repeated measures) to assess genetic influences on changes in cortical thinning. We find considerable thinning of the cortex between over this three year interval (on average 0.05 mm; 1.5%), particularly in the frontal poles, and orbitofrontal, paracentral, and occipital cortices. Cortical thinning was highly heritable at age 9 and age 12, and the degree of genetic influence differed for the various areas of the brain. One genetic factor affected left inferior frontal (Broca's area), and left parietal (Wernicke's area) thinning; a second factor influenced left anterior paracentral (sensory-motor) thinning. Two factors influenced cortical thinning in the frontal poles: one of decreasing influence over time, and another independent genetic factor emerging at age 12 in left and right frontal poles. Thus, thinning of the cerebral cortex is heritable in children between the ages 9 and 12. Furthermore, different genetic factors are responsible for variation in cortical thickness at ages 9 and 12, with independent genetic factors acting on cortical thickness across time and between various brain areas during childhood brain development.
NeuroImage 12/2011; 59(4):3871-80. · 5.89 Impact Factor
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M D Klok,
E J Giltay,
A J W Van der Does,
J M Geleijnse,
N Antypa,
B W J H Penninx,
E J C de Geus,
G Willemsen, D I Boomsma,
N van Leeuwen,
F G Zitman,
E R de Kloet,
R H DeRijk
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ABSTRACT: Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ~0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.Keywords: cortisol; depression; female prevalence; mineralocorticoid receptor; optimism; single-nucleotide polymorphisms
Translational Psychiatry. 11/2011; 1(12):e62.
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C M Middeldorp,
M H M de Moor,
L M McGrath,
S D Gordon,
D H Blackwood,
P T Costa,
A Terracciano,
R F Krueger,
E J C de Geus,
D R Nyholt, [......],
G R Abecasis,
I J Deary,
K R|[auml]|ikk|[ouml]|nen,
L J Bierut,
N G Martin,
N R Wray,
C M van Duijn,
J W Smoller,
B W J H Penninx, D I Boomsma
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ABSTRACT: The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13 835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case–Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ~0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.Keywords: bipolar disorder; genetic correlation; genome-wide association; polygenic score analysis; personality-major depression
Translational Psychiatry. 09/2011; 1(10):e50.
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N Amin,
E Byrne,
J Johnson,
G Chenevix-Trench,
S Walter,
I M Nolte,
J M Vink,
R Rawal,
M Mangino,
A Teumer, [......],
H Tiemeier,
B H R Wolfenbuttel,
B A Oostra,
A C Heath,
E Wichmann,
T D Spector,
H J Grabe, D I Boomsma,
N G Martin,
C M van Duijn
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ABSTRACT: Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).
Molecular psychiatry 08/2011; 17(11):1116-29. · 15.05 Impact Factor
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A Demirkan,
B W J H Penninx,
K Hek,
N R Wray,
N Amin,
Y S Aulchenko,
R van Dyck,
E J C de Geus,
A Hofman,
A G Uitterlinden, [......],
W A Nolen,
B A Oostra,
P F Sullivan,
G Willemsen,
F G Zitman,
H Tiemeier,
A C J W Janssens, D I Boomsma,
C M van Duijn,
C M Middeldorp
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ABSTRACT: The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to ∼0.7% of the variance in depression in Rotterdam Study and up to ∼1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples.
Molecular psychiatry 07/2011; 16(7):773-83. · 15.05 Impact Factor
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ABSTRACT: Traumatic life events are generally more common in patients with borderline personality disorder (BPD) than in non-patients or patients with other personality disorders. This study investigates whether exposure to life events moderates the genetic architecture of BPD features. As the presence of genotype-environment correlation (rGE) can lead to spurious findings of genotype-environment interaction (G × E), we also test whether BPD features increase the likelihood of exposure to life events.
The extent to which an individual is at risk to develop BPD was assessed with the Personality Assessment Inventory - Borderline features scale (PAI-BOR). Life events under study were a divorce/break-up, traffic accident, violent assault, sexual assault, robbery and job loss. Data were available for 5083 twins and 1285 non-twin siblings. Gene-environment interaction and correlation were assessed by using structural equation modelling (SEM) and the co-twin control design.
There was evidence for both gene-environment interaction and correlation. Additive genetic influences on BPD features interacted with the exposure to sexual assault, with genetic variance being lower in exposed individuals. In individuals who had experienced a divorce/break-up, violent assault, sexual assault or job loss, environmental variance for BPD features was higher, leading to a lower heritability of BPD features in exposed individuals. Gene-environment correlation was present for some life events. The genes that influence BPD features thus also increased the likelihood of being exposed to certain life events.
To our knowledge, this study is the first to test the joint effect of genetic and environmental influences and the exposure to life events on BPD features in the general population. Our results indicate the importance of both genetic vulnerability and life events.
Psychological Medicine 04/2011; 41(4):849-60. · 6.16 Impact Factor
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A M C Simonis-Bik, D I Boomsma,
J M Dekker,
M Diamant,
E J C de Geus,
L M 't Hart,
R J Heine,
M H H Kramer,
J A Maassen,
A Mari,
A Tura,
G Willemsen,
E M W Eekhoff
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ABSTRACT: We estimated the heritability of individual differences in beta cell function after a mixed meal test designed to assess a wide range of classical and model-derived beta cell function parameters.
A total of 183 healthy participants (77 men), recruited from the Netherlands Twin Register, took part in a 4 h protocol, which included a mixed meal test. Participants were Dutch twin pairs and their siblings, aged 20 to 49 years. All members within a family were of the same sex. Insulin sensitivity, insulinogenic index, insulin response and postprandial glycaemia were assessed, as well as model-derived parameters of beta cell function, in particular beta cell glucose sensitivity and insulin secretion rates. Genetic modelling provided the heritability of all traits. Multivariate genetic analyses were performed to test for overlap in the genetic factors influencing beta cell function, waist circumference and insulin sensitivity.
Significant heritabilities were found for insulinogenic index (63%), beta cell glucose sensitivity (50%), insulin secretion during the first 2 h postprandial (42-47%) and postprandial glycaemia (43-52%). Genetic factors influencing beta cell glucose sensitivity and insulin secretion during the first 30 postprandial min showed only negligible overlap with the genetic factors that influence waist circumference and insulin sensitivity.
The highest heritability for postprandial beta cell function was found for the insulinogenic index, but the most specific indices of heritability of beta cell function appeared to be beta cell glucose sensitivity and the insulin secretion rate during the first 30 min after a mixed meal.
Diabetologia 02/2011; 54(5):1043-51. · 6.81 Impact Factor
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A Terracciano,
T Esko,
A R Sutin,
M H M de Moor,
O Meirelles,
G Zhu,
T Tanaka,
I Giegling,
T Nutile,
A Realo, [......],
G R Abecasis, D I Boomsma,
M Ciullo,
P T Costa,
L Ferrucci,
N G Martin,
A Metspalu,
D Rujescu,
D Schlessinger,
M Uda
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ABSTRACT: The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 × 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed α-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders.
Translational psychiatry. 01/2011; 1:e49.
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M H M de Moor,
P T Costa,
A Terracciano,
R F Krueger,
E J C de Geus,
T Toshiko,
B W J H Penninx,
T Esko,
P A F Madden,
J Derringer, [......],
A C J W Janssens,
B A Oostra,
A Metspalu,
G R Abecasis,
I J Deary,
K Räikkönen,
L J Bierut,
N G Martin,
C M van Duijn, D I Boomsma
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ABSTRACT: Personality can be thought of as a set of characteristics that influence people's thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in 10 discovery samples (17,375 adults) and five in silico replication samples (3294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data of ≈ 2.4M single-nucleotide polymorphisms (SNPs; directly typed and imputed using HapMap data) were available. In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P=2.8 × 10(-8) and 3.1 × 10(-8)) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P=4.9 × 10(-8)). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.
Molecular psychiatry 12/2010; 17(3):337-49. · 15.05 Impact Factor
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N R Wray,
M L Pergadia,
D H R Blackwood,
B W J H Penninx,
S D Gordon,
D R Nyholt, S Ripke,
D J MacIntyre,
K A McGhee,
A W Maclean, [......],
E M Byrne,
S E Medland,
D J Statham,
A K Henders,
A C Heath,
G W Montgomery,
N G Martin, D I Boomsma,
P A F Madden,
P F Sullivan
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ABSTRACT: Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.Keywords: major depressive disorder; depression; genome-wide association study; CACNA1C; ADCY3; GAL
Molecular Psychiatry 11/2010; 17(1):36-48. · 13.67 Impact Factor
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N R Wray,
M L Pergadia,
D H R Blackwood,
B W J H Penninx,
S D Gordon,
D R Nyholt,
S Ripke,
D J MacIntyre,
K A McGhee,
A W Maclean, [......],
E M Byrne,
S E Medland,
D J Statham,
A K Henders,
A C Heath,
G W Montgomery,
N G Martin, D I Boomsma,
P A F Madden,
P F Sullivan
[show abstract]
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ABSTRACT: Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.
Molecular psychiatry 11/2010; 17(1):36-48. · 15.05 Impact Factor
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ABSTRACT: Our aim was to provide an overview of prospective studies that have addressed the association between attention problems (AP, i.e. symptoms of hyperactivity and inattentiveness) and academic achievement (AA).
We conducted a systematic search in the literature. Normal population studies and clinical studies were included. The methodological quality of each study was evaluated by objective criteria. A best evidence synthesis was used to determine the strengths of the association.
Sixteen studies were included. We found convincing evidence for a negative association between AP and AA. After controlling for intelligence, comorbidity, and socioeconomic status (SES), the association between the hyperactive symptoms of AP and AA was non-significant in two studies.
Children with AP are at risk for lower AA and subsequent adverse outcomes later in life. Interventions in affected children should focus on their behavioural and educational development.
Acta Psychiatrica Scandinavica 10/2010; 122(4):271-84. · 4.22 Impact Factor
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C M Middeldorp,
M C T Slof-Op 't Landt,
S E Medland,
C E M van Beijsterveldt,
M Bartels,
G Willemsen,
J-J Hottenga,
E J C de Geus,
H E D Suchiman,
C V Dolan,
M C Neale,
P E Slagboom, D I Boomsma
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ABSTRACT: There are two major hypotheses regarding the etiology of anxiety and depression: the mono-amine hypothesis and the hypothesis of an abnormal stress response acting partly via reduced neurogenesis. Association studies have focused on genes involved in these processes, but with inconclusive results. This study investigated the effect of 45 single nucleotide polymorphisms (SNPs) in genes encoding for serotonin receptors 1A, 1D, 2A, catechol-O-methyltransferase (COMT), tryptophane hydroxylase type 2 (TPH2), brain derived neurotrophic factor (BDNF), PlexinA2 and regulators of G-protein-coupled signaling (RGS) 2, 4, 16. Anxious depression (A/D) symptoms were assessed five times in 11 years in over 11 000 adults with 1504 subjects genotyped and at age 7, 10, 12 and during adolescence in over 20 000 twins with 1078 subjects genotyped. In both cohorts, a longitudinal model with one latent factor loading on all A/D measures over time was analysed. The genetic association effect modeled at the level of this latent factor was 60% and 70% heritable in the children and adults, respectively, and explained around 50% of the total phenotypic variance. Power analyses showed that the samples contained 80% power to detect an effect explaining between 1.4% and 3.6% of the variance. However, no SNP showed a consistent effect on A/D. To conclude, this longitudinal study in children and adults found no association of SNPs in the serotonergic system or core regulators of neurogenesis with A/D. Overall, there has been no convincing evidence, so far, for a role of genetic variation in these pathways in the development of anxiety and depression.
Genes Brain and Behavior 10/2010; 9(7):808-16. · 3.48 Impact Factor
