Manuel A R Ferreira

Queensland Institute of Medical Research, Brisbane, Queensland, Australia

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Publications (42)385.72 Total impact

  • Manuel A R Ferreira
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    ABSTRACT: Asthma and hay fever are likely to share hundreds if not thousands of genetic risk variants. Despite this, the extent to which the power to identify shared risk variants could be improved by considering information from both diseases when designing or analyzing genetic studies has not been studied in detail. Simulations were performed to quantify the power to detect an association between case-control status and a bi-allelic risk variant shared between asthma and hay fever across a range of disease and genetic models, as well as different ascertainment and analytical strategies. For a fixed sample size, when designing a new genome-wide association study (GWAS), selecting for genotyping cases with both asthma and hay fever (A+H+), and controls with neither disease (A-H-) was the study design that provided the greatest power to identify a shared risk variant. On the other hand, when analyzing an existing GWAS, power was greatest across a wide range of scenarios, when cases were defined as individuals who suffered from either disease (A+ or H+) and controls as those who suffered from neither (A-H-). Bivariate analysis of asthma and hay fever provided comparable but slightly decreased power. In conclusion, new GWAS can be designed and existing GWAS reanalyzed more efficiently to identify risk variants for allergic disease by using ascertainment or analytical strategies that consider both asthma and hay fever information.
    Twin Research and Human Genetics 10/2014; · 1.92 Impact Factor
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    Olivia R. Ferry, David L. Duffy, Manuel A. R. Ferreira
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    ABSTRACT: Prevention strategies that delay the onset of asthma may improve clinical outcomes. To identify early life environmental exposures associated with asthma age-of-onset and potential genetic modifiers of these exposures, we studied 1085 subjects with physician-diagnosed asthma and disease onset at or after age two. Subjects reported retrospectively on their exposure to 17 environmental factors before the age of two. The presence of individual or combinations of these early life exposures was then tested for association with variation in asthma age-of-onset. For exposures significantly associated with age-of-onset, we tested if 26 single nucleotide polymorphisms (SNP) with an established association with allergic disease significantly modified the effect of the exposure. Five environmental exposures were significantly associated with variation in asthma age-of-onset after correction for multiple testing: carpet at home (P = 6 × 10−5), a serious chest illness (P = 10−4), father a cigarette smoker (P = 6 × 10−4) and direct exposure to father's smoking (P = 3 × 10−4). Individuals with early childhood asthma onset, between the ages of two and six, were 1.4-fold (CI 1.1–1.9) more likely to report having lived in a house with carpet and 2.1-fold (CI 1.3–3.5) more likely to report suffering a serious chest illness before the age of two, than asthmatics with later disease onset. We further found these individual risks to increase to 3.2-fold (CI 1.7–6.0) if carpet exposure and suffering a serious chest illness co-occurred before age two. Paternal smoking exposures were less likely to be reported by asthmatics with early when compared to later disease onset (OR 0.5, CI 0.3–0.7). There were no significant SNP interactions with these environmental exposures after correction for multiple testing. Our results suggest that disease onset in individuals at a high-risk of developing asthma can potentially be delayed by avoiding exposure to carpet at home and preventing serious chest illnesses during the first 2 years of life.
    Immunity, Inflammation and Disease. 07/2014;
  • Clara S Tang, Manuel A R Ferreira
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    ABSTRACT: MOTIVATION: Canonical correlation analysis (CCA) measures the association between two sets of multidimensional variables. We reasoned that CCA could provide an efficient and powerful approach for both univariate and multivariate gene-based tests of association without the need for permutation testing. RESULTS: Compared with a commonly used permutation-based approach, CCA (i) is faster; (ii) has appropriate type-I error rate for normally distributed quantitative traits; (iii) provides comparable power for small to medium-sized genes (<100 kb); (iv) provides greater power when the causal variants are uncommon; (v) provides considerably less power for larger genes (≥100 kb) when the causal variants have a broad minor allele frequency (MAF) spectrum. Application to a GWAS of leukocyte levels identified SAFB and a histone gene cluster as novel putative loci harboring multiple independent variants regulating lymphocyte and neutrophil counts.
    Bioinformatics 01/2012; 28(6):845-50. · 4.62 Impact Factor
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    Clara S Tang, Manuel A R Ferreira
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    ABSTRACT: In many published genome-wide association studies (GWAS), the top few strongly associated variants are often located in or near known genes. This observation raises the more general hypothesis that variants nominally associated with a phenotype are more likely to overlap genes than those not associated with a phenotype. We developed a simple approach - named GENe OVerlap Analysis (GENOVA) - to formally test this hypothesis. This approach includes two steps. First, we define largely independent groups of highly correlated SNPs (or "clumps") and classify each clump as intersecting a gene or not. Second, we determine how strongly associated each clump is with the phenotype and use logistic regression to formally test the hypothesis that clumps associated with the phenotype are more likely to intersect genes. Simulations suggest that the power of GENOVA is affected by at least three factors: GWAS sample size, the gene boundaries used to define gene-intersecting clumps and the P-value threshold used to define phenotype-associated clumps. We applied GENOVA to results from three recent GWAS meta-analyses of height, body mass index (BMI) and waist-hip ratio (WHR) conducted by the GIANT consortium. SNPs associated with variation in height were 1.44-fold more likely to be in or near genes than SNPs not associated with height (P = 5 x 10⁻²⁸). A weaker association was observed for BMI (1.09-fold, P = 0.008) and WHR (1.09-fold, P = 0.014). GENOVA is implemented in C++ and is freely available at https://genepi.qimr.edu.au/staff/manuelF/genova/main.html.
    Statistical Applications in Genetics and Molecular Biology 01/2012; 11(3):Article 6. · 1.52 Impact Factor
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    ABSTRACT: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10(-8)) and three variants reported as suggestive (P<5×10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P(Stage1+Stage2) = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P(Stage1+Stage2) = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
    PLoS ONE 01/2012; 7(9):e44008. · 3.53 Impact Factor
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    ABSTRACT: Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P=4.8 × 10−7). Five other loci were associated with P
    European journal of human genetics: EJHG 10/2011; 19(10):1109. · 3.56 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have become a major strategy for genetic dissection of human complex diseases. Analysing multiple phenotypes jointly may improve both our ability to detect genetic variants with multiple effects and our understanding of their common features. Allelic associations for multiple biochemical traits (serum alanine aminotransferase, aspartate aminotransferase, butrylycholinesterase (BCHE), C-reactive protein (CRP), ferritin, gamma glutamyltransferase (GGT), glucose, high-density lipoprotein cholesterol (HDL), insulin, low-density lipoprotein cholesterol (LDL), triglycerides and uric acid), and body-mass index, were examined. We aimed to identify common genetic variants affecting more than one of these traits using genome-wide association analysis in 2548 adolescents and 9145 adults from 4986 Australian twin families. Multivariate and univariate associations were performed. Multivariate analyses identified eight loci, and univariate association analyses confirmed two loci influencing more than one trait at p < 5 × 10-8. These are located on chromosome 8 (LPL gene affecting HDL and triglycerides) and chromosome 19 (TOMM40/APOE-C1-C2-C4 gene cluster affecting LDL and CRP). A locus on chromosome 12 (OASL gene) showed effects on GGT, LDL and CRP. The loci on chromosomes 12 and 19 unexpectedly affected LDL cholesterol and CRP in opposite directions. We identified three possible loci that may affect multiple traits and validated 17 previously-reported loci. Our study demonstrated the usefulness of examining multiple phenotypes jointly and highlights an anomalous effect on CRP, which is increasingly recognised as a marker of cardiovascular risk as well as of inflammation.
    BMC Medical Genetics 09/2011; 12:123. · 2.45 Impact Factor
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    ABSTRACT: We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.
    The Lancet 09/2011; 378(9795):1006-14. · 39.21 Impact Factor
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    ABSTRACT: We recently mapped a quantitative trait locus for monocyte counts to chromosome 9q31 (rs7023923). Here we extend this work by showing with two independent approaches that rs7023923 regulates the expression levels of the nearby LPAR1 gene (P<0.0001), specifically implicating this gene in monocyte development. Furthermore, we tested 10 additional loci identified in the original analysis for replication in 1,122 individuals and confirm that rs6740847 near the alpha-4-integrin gene (ITGA4) associates with variation in monocyte counts (combined P=2.7×10−10). This variant is in complete linkage disequilibrium (r2=1) with a previously reported eQTL for ITGA4 (rs2124440), indicating that this is the likely causal gene in the region. Our results indicate that rs7023923 and rs6740847 respectively upregulate LPAR1 and downregulate ITGA4 expression and this increases the number of monocytes circulating in the peripheral blood. Further studies that investigate the downstream mechanism involved and the impact on immune function are warranted. Hum Mutat 32:1–4, 2011. © 2011 Wiley-Liss, Inc.
    Human Mutation 07/2011; 32(8):873 - 876. · 5.05 Impact Factor
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    ABSTRACT: Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P = 4.8 × 10⁻⁷). Five other loci were associated with P < 10⁻⁵, most notably the chemokine CXC motif ligand 14 (CXCL14) gene (rs31263, P = 7.8 × 10⁻⁶). We found no evidence for association with the specific risk variants reported recently for PDE4D, DENND1B and ILR1L1. However, a variant in IL1RL1 that is in low linkage disequilibrium with that reported previously was associated with asthma risk after accounting for all variants tested (rs10197862, gene wide P = 0.01). This association replicated convincingly in an independent cohort (P = 2.4 × 10⁻⁴). A 300-kb deletion on chromosome 17q21 was associated with asthma risk, but this did not reach experiment-wide significance. Asthma cases and controls had comparable CNV rates, length and number of genes affected by deletions or duplications. In conclusion, we confirm the association between asthma risk and variants in ORMDL3 and identify a novel risk variant in IL1RL1. Follow-up of the 17q21 deletion in larger cohorts is warranted.
    European journal of human genetics: EJHG 12/2010; 19(4):458-64. · 3.56 Impact Factor
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    ABSTRACT: Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (>or=3024 families with >or=10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21-p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3-q24 in all families for SPT and three other regions in European families (2q32-q34 for EOS, 5q23-q33 for SPTQ and 17q12-q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11-3q21, whereas between-study heterogeneity was detected for asthma in 2p22-p13 and 6p21, and for atopic asthma in 1q23-q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies.
    European journal of human genetics: EJHG 06/2010; 18(6):700-6. · 3.56 Impact Factor
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    ABSTRACT: Several studies have documented a profile of elevated scores on the Attention Problems, Aggressive Behavior and Anxious/Depressed scales of the Child Behavior Checklist (CBCL) in youth with bipolar disorder. The sum of these scales, referred to as the CBCL Juvenile Bipolar Disorder (JBD) phenotype, has modest diagnostic utility, and high scores are associated with severity of psychopathology and poor outcome. Recently, a genomewide linkage scan of this measure in ADHD sibling pairs revealed a region of suggestive linkage on chromosome 2q21. The current study aimed to further identify quantitative trait loci that influence the CBCL-JBD phenotype by using a dense and thus, arguably, more powerful set of single-nucleotide polymorphism markers in a different ADHD sibling pair sample. Subjects were 765 individuals from 154 families with CBCL data enrolled in a linkage study of ADHD. Linkage analyses were completed using a multipoint maximum likelihood variance components approach implemented using the statistical program SOLAR. Heritability of the CBCL-JBD phenotype was estimated at .71. Although no regions of the genome surpassed empirically derived criteria for significant linkage (p = .000038), peaks on 1p21.1 (p = .00037; LOD = 2.76), 6p21.3 (p = .00054; LOD =2.60), and 8q21.13 (p = .00081; LOD = 2.44) surpassed the threshold for suggestive linkage (p = .002). These regions have been highlighted in genomewide scans of bipolar disorder in adults, schizophrenia, autism, and ADHD. Findings raise the possibility that genes in these regions influence variation on the CBCL-JBD scale and the emotional and behavioral dysregulation associated with severe psychopathology.
    Journal of the American Academy of Child and Adolescent Psychiatry 04/2010; 49(4):378-87. · 6.97 Impact Factor
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    ABSTRACT: Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte subsets, measured in 2538 individuals from the general population, including CD4+ T cells, CD8+ T cells, CD56+ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p = 2.1 x 10(-28)). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p = 6.1 x 10(-14)). The MHC association with CD4:CD8 replicated convincingly (p = 1.4 x 10(-9)) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class I cluster and influences CD8 levels, whereas the second is located in the class II cluster and regulates CD4 levels. Jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class II variants are associated with type-1 diabetes, suggesting that genetic variation at the MHC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.
    The American Journal of Human Genetics 01/2010; 86(1):88-92. · 11.20 Impact Factor
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    ABSTRACT: Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining approximately 6% of variance (p=1.5x10(-31)). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations.
    The American Journal of Human Genetics 11/2009; 85(5):750-5. · 11.20 Impact Factor
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    ABSTRACT: We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791, combined P = 1.5 x 10(-20)), transferrin saturation (combined P = 2.2 x 10(-23)) and erythrocyte mean cell volume (MCV, combined P = 1.1 x 10(-10)). We also find suggestive evidence of association with blood hemoglobin levels (combined P = 5.3 x 10(-7)). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis.
    Nature Genetics 10/2009; 41(11):1173-5. · 29.65 Impact Factor
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    ABSTRACT: Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p=8.9x10(-14)). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p=1.2x10(-9), 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p=5.3x10(-9), 0.6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values=0.001, 9.9x10(-5), and 7x10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.
    The American Journal of Human Genetics 10/2009; 85(5):745-9. · 11.20 Impact Factor
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    ABSTRACT: We present a method for testing overrepresentation of biological pathways, indexed by gene-ontology terms, in lists of significant SNPs from genome-wide association studies. This method corrects for linkage disequilibrium between SNPs, variable gene size, and multiple testing of nonindependent pathways. The method was applied to the Wellcome Trust Case-Control Consortium Crohn disease (CD) data set. At a general level, the biological basis of CD is relatively well known for a complex genetic trait, and it thus acted as a test of the method. The method, known as ALIGATOR (Association LIst Go AnnoTatOR), successfully detected biological pathways implicated in CD. The method was also applied to a meta-analysis of bipolar disorder, and it implicated the modulation of transcription and cellular activity, including that which occurs via hormonal action, as an important player in pathogenesis.
    The American Journal of Human Genetics 07/2009; 85(1):13-24. · 11.20 Impact Factor
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    ABSTRACT: Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%
    Nature 06/2009; 460(7256):748-752. · 42.35 Impact Factor
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    ABSTRACT: Family and twin studies suggest that a range of neurocognitive traits index the inherited liability to ADHD; however, the utility of such measures as endophenotypes in molecular genetic studies remains largely untested. The current article examined whether the inclusion of neurocognitive measures in a genomewide linkage analysis of ADHD could aid in identifying QTL linked to the behavioral symptoms of the condition. Data were from an affected sibling pair linkage study of DSM-IV ADHD conducted at Massachusetts General Hospital. The sample included 1,212 individuals from 271 families. ADHD symptoms were assessed with the K-SADS-E. The neurocognitive battery included Wechsler Intelligence Scales subtests, the Stroop, the Wisconsin Card Sorting Test (WCST), the Rey-Osterreith Complex Figure, a working memory CPT, the CVLT and WRAT-III subscales. Evidence for linkage was assessed using a simulation-based method that combines information from univariate analyses into the equivalent of a multivariate test. After correction for multiple trait testing, a region on chromosome 3q13 showed suggestive linkage to all neurocognitive traits examined and inattention symptoms of ADHD. The second highest peak occurred on 22q12 but showed linkage to a single subscale of the WCST. In univariate analysis, this region retained criteria for suggestive linkage to this measure after correction for multiple trait testing. Our primary findings raise the possibility that one or more genes on 3q13 influence neurocognitive functions and behavioral symptoms of inattention. Overall, these data support the utility of neurocognitive traits as ADHD endophenotypes, but also highlight their limited genetic overlap with the disorder. © 2008 Wiley-Liss, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2009; 150B(5):751 - 751. · 3.27 Impact Factor
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    ABSTRACT: Lithium remains a first-line treatment for bipolar disorder, but the mechanisms by which it prevents the recurrence of mood episodes are not known. The authors utilized data from a genomewide association study to examine associations between single nucleotide polymorphisms (SNPs) and the outcome of lithium treatment in two cohorts of patients with bipolar I disorder or bipolar II disorder. The hazard for mood episode recurrence was examined among 1,177 patients with bipolar I disorder or bipolar II disorder, including 458 individuals treated with lithium carbonate or citrate, who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort. SNPs showing the greatest evidence of association in Cox regression models were then examined for association with positive lithium response among 359 bipolar I or II disorder patients treated with lithium carbonate or citrate in a second cohort from the University College London. The strongest association in the STEP-BD cohort (minimum p=5.5 x 10(-7)) was identified for a region on chromosome 10p15 (rs10795189). Of the regions showing suggestive evidence (p<5 x 10(-4)) of association with lithium response, five were further associated with positive lithium response in the University College London cohort, including SNPs in a region on chromosome 4q32 spanning a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2. Multiple novel loci merit further examination for association with lithium response in bipolar disorder patients, including one region that spans the GRIA2 gene, for which expression has been shown to be regulated by lithium treatment.
    American Journal of Psychiatry 06/2009; 166(6):718-25. · 14.72 Impact Factor

Publication Stats

10k Citations
385.72 Total Impact Points

Institutions

  • 2004–2014
    • Queensland Institute of Medical Research
      • Genetic Epidemiology Laboratory
      Brisbane, Queensland, Australia
  • 2003–2010
    • Royal Brisbane Hospital
      Brisbane, Queensland, Australia
  • 2007–2009
    • Massachusetts General Hospital
      • • Department of Psychiatry
      • • Center for Human Genetic Research
      Boston, MA, United States
    • Harvard Medical School
      • Department of Psychiatry
      Boston, MA, United States
    • Royal Prince Alfred Hospital
      Camperdown, New South Wales, Australia
  • 2006
    • University of Queensland
      Brisbane, Queensland, Australia