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M Li,
X-J Luo,
M Rietschel,
C M Lewis,
M Mattheisen,
B Müller-Myhsok,
S Jamain,
M Leboyer,
M Landén,
P M Thompson, [......],
H Walter,
A Heinz,
F Bellivier,
J L Stein,
S E Medland,
A A Vasquez,
D P Hibar,
B Franke,
N G Martin,
M J Wright
Molecular psychiatry 05/2013; · 15.05 Impact Factor
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M Li,
X-J Luo,
M Rietschel,
C M Lewis,
M Mattheisen,
B Müller-Myhsok,
S Jamain,
M Leboyer,
M Landén,
P M Thompson, [......],
A Heinz,
F Bellivier,
J L Stein,
S E Medland,
A Arias Vasquez,
D P Hibar,
B Franke,
N G Martin,
M J Wright,
B Su
[show abstract]
[hide abstract]
ABSTRACT: Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64 888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.Molecular Psychiatry advance online publication, 9 April 2013; doi:10.1038/mp.2013.37.
Molecular psychiatry 04/2013; · 15.05 Impact Factor
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A L Collins,
Y Kim,
J P Szatkiewicz,
R J Bloom,
C E Hilliard,
C R Quackenbush,
S Meier,
F Rivas,
F Mayoral,
S Cichon,
M M Nöthen,
M Rietschel, P F Sullivan
Molecular psychiatry 12/2012; · 15.05 Impact Factor
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S E Bergen,
C T O'Dushlaine,
S Ripke,
P H Lee,
D M Ruderfer,
S Akterin,
J L Moran,
K D Chambert,
R E Handsaker,
L Backlund,
U Ösby,
S McCarroll,
M Landen,
E M Scolnick,
P K E Magnusson,
P Lichtenstein,
C M Hultman,
S M Purcell,
P Sklar, P F Sullivan
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.
Molecular psychiatry 06/2012; 17(9):880-6. · 15.05 Impact Factor
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J J Crowley,
C E Hilliard,
Y Kim,
M B Morgan,
L R Lewis,
D M Muzny,
A C Hawes,
A Sabo,
D A Wheeler,
J A Lieberman, P F Sullivan,
R A Gibbs
Molecular psychiatry 04/2012; · 15.05 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder of complex etiology. Although strong evidence supports the causal role of genetic factors, environmental risk factors have also been implicated. This study used a co-twin-control design to investigate low birth weight as a risk factor for ASD.
We studied a population-based sample of 3715 same-sex twin pairs participating in the Child and Adolescent Twin Study of Sweden (CATSS). ASD was assessed using a structured parent interview for screening of ASD and related developmental disorders, based on DSM-IV criteria. Birth weight was obtained from medical birth records maintained by the Swedish Medical Birth Registry.
Twins lower in birth weight in ASD-discordant twin pairs (n=34) were more than three times more likely to meet criteria for ASD than heavier twins [odds ratio (OR) 3.25]. Analyses of birth weight as a continuous risk factor showed a 13% reduction in risk of ASD for every 100 g increase in birth weight (n=78). Analysis of the effect of birth weight on ASD symptoms in the entire population (most of whom did not have ASD) showed a modest association. That is, for every 100 g increase in birth weight, a 2% decrease in severity of ASD indexed by scores on the Autism - Tics, attention-deficit hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC) inventory would be expected in the sample as a whole.
The data were consistent with the hypothesis that low birth weight confers risk to ASD. Thus, although genetic effects are of major importance, a non-genetic influence associated with birth weight may contribute to the development of ASD.
Psychological Medicine 12/2011; 42(5):1091-102. · 6.16 Impact Factor
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X Chen,
G Lee,
B S Maher,
A H Fanous,
J Chen,
Z Zhao,
A Guo,
E van den Oord, P F Sullivan,
J Shi, [......],
A McQuillin,
J Pimm,
C Hultman,
P Lichtenstein,
P Sklar,
S M Purcell,
E Scolnick,
D St Clair,
D H R Blackwood,
K S Kendler
[show abstract]
[hide abstract]
ABSTRACT: We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.
Molecular psychiatry 11/2011; 16(11):1117-29. · 15.05 Impact Factor
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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
[show abstract]
[hide abstract]
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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E S Lips,
L N Cornelisse,
R F Toonen,
J L Min,
C M Hultman,
P A Holmans,
M C O'Donovan,
S M Purcell,
A B Smit,
M Verhage, P F Sullivan,
P M Visscher,
D Posthuma
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ∼1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P=7.6 × 10(-11)) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P<0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P=2.0 × 10(-4)), excitability (P=9.0 × 10(-4)) and cell adhesion and trans-synaptic signaling (P=2.4 × 10(-3)). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.
Molecular psychiatry 09/2011; 17(10):996-1006. · 15.05 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Candidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS).
We describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC).
SZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p values in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1 and SLC6A4) had no notable ISC results.
We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively.
Psychological Medicine 08/2011; 42(3):607-16. · 6.16 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
[show abstract]
[hide abstract]
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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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]
[hide abstract]
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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J J Crowley,
D E Adkins,
A L Pratt,
C R Quackenbush,
E J van den Oord,
S S Moy,
K C Wilhelmsen,
T B Cooper,
M A Bogue,
H L McLeod, P F Sullivan
[show abstract]
[hide abstract]
ABSTRACT: Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (TD) (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci, which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. In all, 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg kg(-1) per day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs; the mouse analog of TD) and other movement phenotypes derived from open-field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90 and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS). Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was ∼0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.
The Pharmacogenomics Journal 11/2010; 12(2):147-55. · 4.54 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]
[hide abstract]
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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K Aberg,
D E Adkins,
Y Liu,
J L McClay,
J Bukszár,
P Jia,
Z Zhao,
D Perkins,
T S Stroup,
J A Lieberman, P F Sullivan,
E J C G van den Oord
[show abstract]
[hide abstract]
ABSTRACT: QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic-induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug-specific genome-wide association studies (GWASs) with 492K single-nucleotide polymorphisms to search for genetic variation mediating antipsychotic-induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness study. Our candidate gene study suggests the involvement of NOS1AP and NUBPL (P-values=1.45 × 10(-05) and 2.66 × 10(-13), respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a Q-value <0.10 (P-value=1.54 × 10(-7), Q-value=0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds, including drugs, environmental toxins and endogenous metabolites, across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic-induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug-induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic-induced QT prolongation.
The Pharmacogenomics Journal 10/2010; 12(2):165-72. · 4.54 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
[show abstract]
[hide abstract]
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.Keywords: depression; anxiety; polygenic; genome-wide association; risk score
Molecular Psychiatry 06/2010; 16(7):773-783. · 13.67 Impact Factor
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Molecular psychiatry 03/2010; 15(5):450-2. · 15.05 Impact Factor
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Y Liu,
D H Blackwood,
S Caesar,
E J C de Geus,
A Farmer,
M A R Ferreira,
I N Ferrier,
C Fraser,
K Gordon-Smith,
E K Green, [......],
A H Young,
T Zandbelt,
D I Boomsma,
N Craddock,
M C O'Donovan,
M J Owen,
B W J H Penninx,
S Purcell,
P Sklar, P F Sullivan
Molecular psychiatry 03/2010; 16(1):2-4. · 15.05 Impact Factor
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F J Bosker,
C A Hartman,
I M Nolte,
B P Prins,
P Terpstra,
D Posthuma,
T van Veen,
G Willemsen,
R H DeRijk,
E J de Geus,
W J Hoogendijk, P F Sullivan,
B W Penninx,
D I Boomsma,
H Snieder,
W A Nolen
[show abstract]
[hide abstract]
ABSTRACT: Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.
Molecular psychiatry 03/2010; 16(5):516-32. · 15.05 Impact Factor
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D E Adkins,
K Aberg,
J L McClay,
J Bukszár,
Z Zhao,
P Jia,
T S Stroup,
D Perkins,
J P McEvoy,
J A Lieberman, P F Sullivan,
E J C G van den Oord
[show abstract]
[hide abstract]
ABSTRACT: Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.
Molecular psychiatry 03/2010; 16(3):321-32. · 15.05 Impact Factor
