Publications (81)618.95 Total impact
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Article: Candidate genes for schizophrenia in a mixed Brazilian population using pooled DNA.
Psychiatry research. 02/2013; -
Article: Investigation of the ZNF804A gene polymorphism with genetic risk for bipolar disorder in attention deficit hyperactivity disorder.
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ABSTRACT: BACKGROUND: Genome-wide association studies (GWAS) have been conducted on many psychiatric disorders. Evidence from large GWAS indicates that the single nucleotide polymorphism (SNP) rs1344706 in the zinc-finger protein 804A gene (ZNF804A) is associated with psychotic disorders including bipolar disorder and schizophrenia. One study also found significant association between rs1344706 and the executive control network of attention. In this study we examine the role of the rs1344706 polymorphism that previously showed association with BD and is known to alter expression of the gene in two clinical family-based ADHD samples from the UK and Taiwan. FINDINGS: To investigate the association between rs1344706 and ADHD, two family samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212) were genotyped using TaqMan SNP genotyping assays and analysed using within-family transmission disequilibrium test. No significant associations were found between rs1344706 polymorphism and ADHD in either of the samples from Taiwan (P = 0.91) and UK (P = 0.41). Even combining the two datasets together the A allele of rs1344706 SNP was still not significantly over-transmitted to affected probands (P = 0.50). Furthermore, there was no evidence of association with the specific symptoms subgroups of inattention or hyperactivity-impulsivity. CONCLUSIONS: In this study we used family-based ADHD data in the UK and Taiwanese population to test for an association between rs1344706 SNP in the ZNF804A gene and ADHD. Results showed no significant association of rs1344706 with ADHD in UK and Taiwanese samples.BMC Research Notes 01/2013; 6(1):29. -
Article: Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
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ABSTRACT: Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.PLoS ONE 01/2013; 8(4):e61365. · 4.09 Impact Factor -
Article: Candidate Genes Expression Profile Associated with Antidepressants Response in the GENDEP Study: Differentiating between Baseline 'Predictors' and Longitudinal 'Targets'.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2013; 38(2):376. · 6.99 Impact Factor -
Article: Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response.
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ABSTRACT: Converging evidence suggests that the activation of the inflammatory cytokine pathway is important in the pathophysiology of unipolar depression. Antidepressants have anti-inflammatory properties and evidence suggests that inter-individual variability in response to antidepressants may reflect genetic differences in the inflammatory cytokine pathway. In particular, protein levels of Tumor Necrosis Factor (TNF) and the SNPs rs1126757 in interleukin-11 (IL11), and rs7801617 in interleukin-6 (IL6), have previously been implicated in the clinical response to the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram. This study investigated the transcription of TNF, IL11 and IL6 as well as genes in the wider inflammatory cytokine pathway both at baseline and after escitalopram treatment in depressed patients who were either clinical "responders" (n=25) or "non-responders" (n=21). Samples were obtained as a subset of the Genome-Based Therapeutic Drugs for Depression (GENDEP) project and response status is based on changes in the Montgomery-Asberg Depression Rating Scores over a 12wk treatment period. Binary logistic regressions revealed significant expression differences at baseline between responders and non-responders in TNF, and after escitalopram treatment in TNF and IL11. Differences in IL11 after treatment were found to be driven by drug-induced allele-specific expression differences relating to rs1126757. Top hits in the wider inflammatory cytokine pathway at both baseline and after escitalopram treatment were found to be targets of TNF. The current study adds substantial support for the role of the inflammatory cytokine pathway in mediating response to the SSRI escitalopram, and is the first to identify TNF and its targets as putative transcriptomic predictors of clinical response.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 11/2012; · 3.68 Impact Factor -
Article: Candidate Genes Expression Profile Associated with Antidepressants Response in the GENDEP Study: Differentiating between Baseline 'Predictors' and Longitudinal 'Targets'
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ABSTRACT: To improve the 'personalized-medicine' approach to the treatment of depression, we need to identify biomarkers that, assessed before starting treatment, predict future response to antidepressants ('predictors'), as well as biomarkers that are targeted by antidepressants and change longitudinally during the treatment ('targets'). In this study, we tested the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-7, IL-8, IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-α), and neuroplasticity (brain-derived neurotrophic factor (BDNF), p11 and VGF), in healthy controls (n=34) and depressed patients (n=74), before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study. Non-responders had higher baseline mRNA levels of IL-1β (+33%), MIF (+48%), and TNF-α (+39%). Antidepressants reduced the levels of IL-1β (-6%) and MIF (-24%), and increased the levels of GR (+5%) and p11 (+8%), but these changes were not associated with treatment response. In contrast, successful antidepressant response was associated with a reduction in the levels of IL-6 (-9%) and of FKBP5 (-11%), and with an increase in the levels of BDNF (+48%) and VGF (+20%)-that is, response was associated with changes in genes that did not predict, at the baseline, the response. Our findings indicate a dissociation between 'predictors' and 'targets' of antidepressant responders. Indeed, while higher levels of proinflammatory cytokines predict lack of future response to antidepressants, changes in inflammation associated with antidepressant response are not reflected by all cytokines at the same time. In contrast, modulation of the GR complex and of neuroplasticity is needed to observe a therapeutic antidepressant effect.Neuropsychopharmacology advance online publication, 19 September 2012; doi:10.1038/npp.2012.191.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2012; · 6.99 Impact Factor -
Article: Dissecting the genetic heterogeneity of depression through age at onset.
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ABSTRACT: Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder. © 2012 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2012; 159B(7):859-68. · 3.70 Impact Factor -
Article: Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder.
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ABSTRACT: Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia. To replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method. In our dataset, rs2251219 was associated with BP (odds ratio [OR] = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 × 10(-9)). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21). There is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder.Biological psychiatry 05/2012; 72(8):645-50. · 8.93 Impact Factor -
Article: Common genetic variants and gene-expression changes associated with bipolar disorder are over-represented in brain signaling pathway genes.
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ABSTRACT: Despite high heritability, the genetic variants influencing bipolar disorder (BD) susceptibility remain largely unknown. Low statistical power to detect the small effect-size alleles believed to underlie much of the genetic risk and possible heterogeneity between cohorts are an increasing concern. Integrative biology approaches might offer advantages over genetic analysis alone by combining different genomic datasets at the higher level of biological processes rather than the level of specific genetic variants or genes. We employed this strategy to identify biological processes involved in BD etiopathology. Three genome-wide association studies and a brain gene-expression study were combined with the Human Protein Reference Database protein-protein interaction network data. We used bioinformatic analysis to search for biological networks with evidence of association on the basis of enrichment among both genetic and differential-expression associations with BD. We identified association with gene networks involved in transmission of nerve impulse, Wnt, and Notch signaling. Three features stand out among these genes: 1) they localized to the human postsynaptic density, which is crucial for neuronal function; 2) their mouse knockouts present altered behavioral phenotypes; and 3) some are known targets of the pharmacological treatments for BD. Genetic and gene-expression associations of BD cluster in discrete regions of the protein-protein interaction network. We found replicated evidence for association for networks involving several interlinked signaling pathways. These genes are promising candidates to generate animal models and pharmacological interventions. Our results demonstrate the potential advantage of integrative biology analyses of BD datasets.Biological psychiatry 04/2012; 72(4):311-7. · 8.93 Impact Factor -
Article: A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.
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ABSTRACT: Changes in brain derived neurotrophic factor (BDNF) expression have been associated with mood disorders and cognitive dysfunction. Transgenic models that overexpress or underexpress BDNF demonstrate similar deficits in cognition and mood. We explored the hypothesis that BDNF expression is controlled by balancing the activity of BDNF promoter IV (BP4) with a negative regulatory region containing a polymorphism associated with cognitive dysfunction and mood disorders. We used comparative genomics, transgenic mouse production, and magnetofection of primary neurons with luciferase reporters and signal transduction agonist treatments to identify novel polymorphic cis-regulatory regions that control BP4 activity. We show that BP4 is active in the hippocampus, the cortex, and the amygdala and responds strongly to stimuli such as potassium chloride, lithium chloride, and protein kinase C agonists. We also identified a highly conserved sequence 21 kilobase 5' of BP4 that we called BE5.2, which contains rs12273363, a polymorphism associated with decreased BDNF expression, mood disorders, and cognitive decline. BE5.2 modulated the ability of BP4 to respond to different stimuli. Intriguingly, the rarer disease associated allele, BE5.2(C), acted as a significantly stronger repressor of BP4 activity than the more common BE5.2(T) allele. This study shows that the C allele of rs12273363, which is associated with mood disorder, modulates BP4 activity in an allele-specific manner following cell depolarization or the combined activity of protein kinase A and protein kinase C pathways. The relevance of these findings to the role of BDNF misexpression in mood disorders and cognitive decline is discussed.Biological psychiatry 01/2012; 71(7):618-26. · 8.93 Impact Factor -
Article: Linkage replication for chromosomal region 13q32 in schizophrenia: evidence from a brazilian pilot study on early onset schizophrenia families.
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ABSTRACT: We report analyses of a Brazilian study of early onset schizophrenia (BEOS) families. We genotyped 22 members of 4 families on a linkage SNP array and report here non-parametric linkage analyses using MERLIN® software. We found suggestive evidence for linkage on two chromosomal regions, 13q32 and 11p15.4. A LOD score of 2.71 was observed at 13q32 with a one LOD interval extending from 60.63-92.35 cM. From simulations, this LOD score gave a genome-wide empirical corrected p = 0.33, after accounting for all markers tested. Similarly 11p15.4 showed the same maximum LOD of 2.71 and a narrower one LOD interval of 4-14 cM. Of these, 13q32 has been reported to be linked to schizophrenia by multiple different studies. Thus, our study provides additional supporting evidence for an aetiological role of variants at 13q32 in schizophrenia.PLoS ONE 01/2012; 7(12):e52262. · 4.09 Impact Factor -
Article: Reduced anxiety and depression-like behaviours in the circadian period mutant mouse afterhours.
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ABSTRACT: Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours. Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder. Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009). Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans.PLoS ONE 01/2012; 7(6):e38263. · 4.09 Impact Factor -
Article: Response to the letter from Dr. Maher and colleagues re. Linkage on Suicidality.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2011; 156B(7):864-5 author reply 866-7. · 3.70 Impact Factor -
Article: A COMT gene haplotype associated with methamphetamine abuse.
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ABSTRACT: Methamphetamine (MAMP) use is highly associated with psychiatric disorders with 12-13% of MAMP-dependent patients experiencing psychotic symptoms. Substance abuse and dependence may primarily involve the mesolimbic pathway and dopaminergic brain structures. It follows that dopaminergic genes, particularly COMT (encoding catechol-O-methyltransferase) and its val158met polymorphism (rs4680), are natural candidates for susceptibility loci to addiction. We have previously found an association with rs4680 and MAMP addiction. We present additional genotyping of rs165599 in 423 cases and 502 controls of a Taiwanese MAMP user sample. We carried out an in-silico evaluation of rs165599 for a possible impact on microRNA binding or UTR stability. We also carried out a review of transcript sequences across the COMT 3'UTR. Genotype counts were (cases/controls): AA 94/110, AG 198/210 and GG 93/109. There were no significant allele or genotype differences between cases and controls for rs165599. However, a haplotype main effect was detected using both rs4680 and rs165599 using the χ²-test in UNPHASED. The global P-value was P=0.0044 with the effect appearing to derive from one haplotype that is underrepresented in cases: A/G for rs4680/rs165599 (haplotype P=0.001). rs165599 is a single nucleotide polymorphism located in the COMT 3' untranslated region (UTR), a noncoding transcript region subject to posttranscriptional down-regulation by mechanisms such as microRNA binding. A review of transcript sequences across the COMT 3'UTR found evidence to suggest antisense interference of COMT from the 3'UTR of the neighbouring 'Armadillo repeat gene deleted in velocardiofacial syndrome' gene.Pharmacogenetics and Genomics 09/2011; 21(11):731-40. · 3.48 Impact Factor -
Article: Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
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ABSTRACT: We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.Nature Genetics 09/2011; 43(10):977-83. · 35.53 Impact Factor -
Article: Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala: implications for obesity, depression and alcoholism.
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ABSTRACT: The expression of the galanin gene (GAL) in the paraventricular nucleus (PVN) and in the amygdala of higher vertebrates suggests the requirement for highly conserved, but unidentified, regulatory sequences that are critical to allow the galanin gene to control alcohol and fat intake and modulate mood. We used comparative genomics to identify a highly conserved sequence that lay 42 kb 5' of the human GAL transcriptional start site that we called GAL5.1. GAL5.1 activated promoter activity in neurones of the PVN, arcuate nucleus and amygdala that also expressed the galanin peptide. Analysis in neuroblastoma cells demonstrated that GAL5.1 acted as an enhancer of promoter activity after PKC activation. GAL5.1 contained two polymorphisms; rs2513280(C/G) and rs2513281(A/G), that occurred in two allelic combinations (GG or CA) where the dominant GG alelle occurred in 70-83 % of the human population. Intriguingly, both SNPs were found to be in LD (R(2) of 0.687) with another SNP (rs2156464) previously associated with major depressive disorder (MDD). Recreation of these alleles in reporter constructs and subsequent magnetofection into primary rat hypothalamic neurones showed that the CA allele was 40 % less active than the GG allele. This is consistent with the hypothesis that the weaker allele may affect food and alcohol preference. The linkage of the SNPs analysed in this study with a SNP previously associated with MDD together with the functioning of GAL5.1 as a PVN and amygdala specific enhancer represent a significant advance in our ability to understand alcoholism, obesity and major depressive disorder.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2011; 36(11):2211-21. · 6.99 Impact Factor -
Article: A genome-wide significant linkage for severe depression on chromosome 3: the depression network study.
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ABSTRACT: The purpose of this study was to find loci for major depression via linkage analysis of a large sibling pair sample. The authors conducted a genome-wide linkage analysis of 839 families consisting of 971 affected sibling pairs with severe recurrent major depression, comprising waves I and II of the Depression Network Study cohort. In addition to examining affected status, linkage analyses in the full data set were performed using diagnoses restricted by impairment severity, and association mapping of hits in a large case-control data set was attempted. The authors identified genome-wide significant linkage to chromosome 3p25-26 when the diagnoses were restricted by severity, which was a maximum LOD score of 4.0 centered at the linkage marker D3S1515. The linkage signal identified was genome-wide significant after correction for the multiple phenotypes tested, although subsequent association mapping of the region in a genome-wide association study of a U.K. depression sample did not provide significant results. The authors report a genome-wide significant locus for depression that implicates genes that are highly plausible for involvement in the etiology of recurrent depression. Despite the fact that association mapping in the region was negative, the linkage finding was replicated by another group who found genome-wide-significant linkage for depression in the same region. This suggests that 3p25-26 is a new locus for severe recurrent depression. This represents the first report of a genome-wide significant locus for depression that also has an independent genome-wide significant replication.American Journal of Psychiatry 05/2011; 168(8):840-7. · 12.54 Impact Factor -
Article: The neuronal transporter gene SLC6A15 confers risk to major depression.
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ABSTRACT: Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting.Neuron 04/2011; 70(2):252-65. · 14.74 Impact Factor -
Article: Gene set analysis and network analysis for genome-wide association studies.
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ABSTRACT: The application of high-throughput genotyping in humans has yielded numerous insights into the genetic basis of human phenotypes and an unprecedented amount of genetic data. Genome-wide association studies (GWAS) have increased in number in recent years, but the variants that have been found have generally explained only a tiny proportion of the estimated genetic contribution to phenotypic variation. This article summarizes the progress made in the development of gene set analysis (GSA) and network analysis for GWAS was a way to identify the underlying molecular processes of human phenotypes. It also highlights some promising findings and indicates future directions that may greatly enhance the analysis and interpretation of GWAS.Cold Spring Harbor Protocols 01/2011; 2011(9). · 4.63 Impact Factor -
Article: Using functional annotation for the empirical determination of Bayes Factors for genome-wide association study analysis.
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ABSTRACT: A genome wide association study (GWAS) typically results in a few highly significant 'hits' and a much larger set of suggestive signals ('near-hits'). The latter group are expected to be a mixture of true and false associations. One promising strategy to help separate these is to use functional annotations for prioritisation of variants for follow-up. A key task is to determine which annotations might prove most valuable. We address this question by examining the functional annotations of previously published GWAS hits. We explore three annotation categories: non-synonymous SNPs (nsSNPs), promoter SNPs and cis expression quantitative trait loci (eQTLs) in open chromatin regions. We demonstrate that GWAS hit SNPs are enriched for these three functional categories, and that it would be appropriate to provide a higher weighting for such SNPs when performing Bayesian association analyses. For GWAS studies, our analyses suggest the use of a Bayes Factor of about 4 for cis eQTL SNPs within regions of open chromatin, 3 for nsSNPs and 2 for promoter SNPs.PLoS ONE 01/2011; 6(4):e14808. · 4.09 Impact Factor
Top co-authors
Top Journals
Institutions
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2012
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Universidade Federal de São Paulo
Guarulhos, Estado de Sao Paulo, Brazil
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2004–2010
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King's College London
- • MRC Social, Genetic and Developmental Psychiatry Centre
- • Institute of Psychiatry
London, ENG, United Kingdom -
ICL
London, ENG, United Kingdom
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2007
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The Kings College
Social Circle, GA, USA
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2006
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Institute of Genetics and Molecular Medicine
Edinburgh, SCT, United Kingdom -
New South Wales Institute of Psychiatry
Sydney, New South Wales, Australia
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1999–2002
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University of Aberdeen
- Institute of Medical Sciences
Aberdeen, SCT, United Kingdom
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