Publications by authors named "Marian Hamshere"

66 Publications

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Nat Genet 2019 05 1;51(5):793-803. Epub 2019 May 1.

Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
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http://dx.doi.org/10.1038/s41588-019-0397-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956732PMC
May 2019

Examining cognition across the bipolar/schizophrenia diagnostic spectrum.

J Psychiatry Neurosci 2018 07;43(4):245-253

From the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK (Lynham, Hubbard, Hamshere, Legge, Owen, Jones, Walters); and the College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK (Tansey).

Background: Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia.

Methods: We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia ( = 558), schizoaffective disorder depressive type ( = 112), schizoaffective disorder type ( = 76), bipolar disorder ( = 78) and healthy participants ( = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis.

Results: Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance ( = 0.07, = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, < 0.001).

Limitations: There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups.

Conclusion: Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019354PMC
July 2018

An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter.

Thyroid 2018 07;28(7):891-901

1 Division of Infection and Immunity, Cardiff University , Cardiff, United Kingdom .

Background: Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC).

Methods: Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM.

Results: Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the PLCB1 gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of "healthy" Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since PLCB1 contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27-59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ = 5.076; p = 0.024. PLCB1 transcript levels were significantly higher in thyroids with the InDel than without (p < 0.02).

Conclusions: The intronic PLCB1 InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.
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http://dx.doi.org/10.1089/thy.2017.0312DOI Listing
July 2018

Examining cognition across the bipolar/schizophrenia diagnostic spectrum.

J Psychiatry Neurosci 2018 Apr 5;43(3):170076. Epub 2018 Apr 5.

From the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK (Lynham, Hubbard, Hamshere, Legge, Owen, Jones, Walters); and the College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK (Tansey).

Background: Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia.

Methods: We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia ( = 558), schizoaffective disorder depressive type ( = 112), schizoaffective disorder type ( = 76), bipolar disorder ( = 78) and healthy participants ( = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis.

Results: Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance ( = 0.07, = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, < 0.001).

Limitations: There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups.

Conclusion: Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries.
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http://dx.doi.org/10.1503/jpn.170076DOI Listing
April 2018

Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.

Nat Genet 2018 03 26;50(3):381-389. Epub 2018 Feb 26.

Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
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http://dx.doi.org/10.1038/s41588-018-0059-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918692PMC
March 2018

Association Between Schizophrenia-Related Polygenic Liability and the Occurrence and Level of Mood-Incongruent Psychotic Symptoms in Bipolar Disorder.

JAMA Psychiatry 2018 01;75(1):28-35

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales.

Importance: Bipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are needed to understand the underlying disease processes and mechanisms.

Objective: To investigate the association between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRSs), and psychotic presentations of BD.

Design, Setting, And Participants: This case-control study in the United Kingdom used multinomial logistic regression to estimate differential PRS associations across categories of cases and controls. Participants included in the final analyses were 4436 cases of BD from the Bipolar Disorder Research Network. These cases were compared with the genotypic data for 4976 cases of schizophrenia and 9012 controls from the Type 1 Diabetes Genetics Consortium study and the Generation Scotland study. Data were collected between January 1, 2000, and December 31, 2013. Data analysis was conducted from March 1, 2016, to February 28, 2017.

Exposures: Standardized PRSs, calculated using alleles with an association threshold of P < .05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, were adjusted for the first 10 population principal components and genotyping platforms.

Main Outcomes And Measures: Multinomial logit models estimated PRS associations with BD stratified by Research Diagnostic Criteria subtypes of BD, by lifetime occurrence of psychosis, and by lifetime mood-incongruent psychotic features. Ordinal logistic regression examined PRS associations across levels of mood incongruence. Ratings were derived from the Schedules for Clinical Assessment in Neuropsychiatry interview and the Bipolar Affective Disorder Dimension Scale.

Results: Of the 4436 cases of BD, 2966 (67%) were female patients, and the mean (SD) age at interview was 46 [12] years. Across clinical phenotypes, there was an exposure-response gradient, with the strongest PRS association for schizophrenia (risk ratio [RR] = 1.94; 95% CI, 1.86-2.01), followed by schizoaffective BD (RR = 1.37; 95% CI, 1.22-1.54), bipolar I disorder subtype (RR = 1.30; 95% CI, 1.24-1.36), and bipolar II disorder subtype (RR = 1.04; 95% CI, 0.97-1.11). Within BD cases, there was an effect gradient, indexed by the nature of psychosis. Prominent mood-incongruent psychotic features had the strongest association (RR = 1.46; 95% CI, 1.36-1.57), followed by mood-congruent psychosis (RR = 1.24; 95% CI, 1.17-1.33) and BD with no history of psychosis (RR = 1.09; 95% CI, 1.04-1.15).

Conclusions And Relevance: For the first time to date, a study shows a polygenic-risk gradient across schizophrenia and BD, indexed by the occurrence and level of mood-incongruent psychotic symptoms.
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http://dx.doi.org/10.1001/jamapsychiatry.2017.3485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833541PMC
January 2018

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Nat Genet 2017 01 21;49(1):27-35. Epub 2016 Nov 21.

Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
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http://dx.doi.org/10.1038/ng.3725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737772PMC
January 2017

Association between polygenic risk scores for attention-deficit hyperactivity disorder and educational and cognitive outcomes in the general population.

Int J Epidemiol 2017 04;46(2):421-428

Medical Research Centre (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.

Background: Children with a diagnosis of attention-deficit hyperactivity disorder ADHD) have lower cognitive ability and are at risk of adverse educational outcomes; ADHD genetic risks have been found to predict childhood cognitive ability and other neurodevelopmental traits in the general population; thus genetic risks might plausibly also contribute to cognitive ability later in development and to educational underachievement.

Methods: We generated ADHD polygenic risk scores in the Avon Longitudinal Study of Parents and Children participants (maximum N : 6928 children and 7280 mothers) based on the results of a discovery clinical sample, a genome-wide association study of 727 cases with ADHD diagnosis and 5081 controls. We tested if ADHD polygenic risk scores were associated with educational outcomes and IQ in adolescents and their mothers.

Results: High ADHD polygenic scores in adolescents were associated with worse educational outcomes at Key Stage 3 [national tests conducted at age 13-14 years; β = -1.4 (-2.0 to -0.8), P  = 2.3 × 10 -6 ), at General Certificate of Secondary Education exams at age 15-16 years (β = -4.0 (-6.1 to -1.9), P  = 1.8 × 10 -4 ], reduced odds of sitting Key Stage 5 examinations at age 16-18 years [odds ratio (OR) = 0.90 (0.88 to 0.97), P  = 0.001] and lower IQ scores at age 15.5 [β = -0.8 (-1.2 to -0.4), P  = 2.4 × 10 -4 ]. Moreover, maternal ADHD polygenic scores were associated with lower maternal educational achievement [β = -0.09 (-0.10 to -0.06), P  = 0.005] and lower maternal IQ [β = -0.6 (-1.2 to -0.1), P  = 0.03].

Conclusions: ADHD diagnosis risk alleles impact on functional outcomes in two generations (mother and child) and likely have intergenerational environmental effects.
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http://dx.doi.org/10.1093/ije/dyw216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424076PMC
April 2017

Reasons for discontinuing clozapine: A cohort study of patients commencing treatment.

Schizophr Res 2016 07 19;174(1-3):113-119. Epub 2016 May 19.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Background: Clozapine is uniquely effective in the management of treatment-resistant schizophrenia (TRS). However, a substantial proportion of patients discontinue treatment and this carries a poor prognosis.

Methods: We investigated the risk factors, reasons and timing of clozapine discontinuation in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. Reasons for discontinuation of clozapine and duration of treatment were obtained from case notes and Cox regression was employed to test the association of baseline clinical factors with clozapine discontinuation.

Results: A total of 142 (45%) patients discontinued clozapine within two years. By studying the reasons for discontinuations due to a patient decision, we found that adverse drug reactions (ADRs) accounted for over half of clozapine discontinuations. Sedation was the most common ADR cited as a reason for discontinuation and the risk of discontinuation due to ADRs was highest in the first few months of clozapine treatment. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR=2.12, 95% CI 1.30-3.47).

Conclusions: Living in a deprived neighbourhood was strongly associated with clozapine discontinuation. Clinical management to reduce the burden of ADRs in the first few months of treatment may have a significant impact and help more patients experience the benefits of clozapine treatment.
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http://dx.doi.org/10.1016/j.schres.2016.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756540PMC
July 2016

Antipsychotic polypharmacy and augmentation strategies prior to clozapine initiation: a historical cohort study of 310 adults with treatment-resistant schizophrenic disorders.

J Psychopharmacol 2016 05 23;30(5):436-43. Epub 2016 Feb 23.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK

Rationale: Antipsychotic polypharmacy (APP) is commonly used in schizophrenia despite a lack of robust evidence for efficacy, as well as evidence of increased rates of adverse drug reactions and mortality.

Objectives: We sought to examine APP and the use of other adjunctive medications in patients with treatment-resistant schizophrenic disorders (ICD-10 diagnoses F20-F29) immediately prior to clozapine initiation, and to investigate clinical and sociodemographic factors associated with APP use in this setting.

Methods: Analysis of case notes from 310 patients receiving their first course of clozapine at the South London and Maudsley NHS Trust (SLaM) was undertaken using the Clinical Record Interactive Search (CRIS) case register. Medication taken immediately prior to clozapine initiation was recorded, and global clinical severity was assessed at time points throughout the year prior to medication assessment using the Clinical Global Impression - Severity scale (CGI-S). Logistic regression was used to investigate factors associated with APP.

Results: The point prevalence of APP prior to clozapine initiation was 13.6% (n=42), with 32.6% of subjects prescribed adjuvant psychotropic medications. APP was associated with increasing number of adjuvant medications (odds ratio (OR) 1.97, 95% confidence interval (CI) 1.27-3.06), concurrent depot antipsychotic prescription (OR 2.64, CI 1.24-5.62), concurrent antidepressant prescription (OR 4.40, CI 1.82-10.63) and a CGI-S over the previous year within the two middle quartiles (Quartile 2 vs 1 OR 6.19, CI 1.81-21.10; Quartile 3 vs 1 OR 4.45, CI 1.29-15.37; Quartile 4 vs 1 OR 1.88, CI 0.45-7.13).

Conclusions: APP and augmentation of antipsychotics with antidepressants, mood stabilizers and benzodiazepines are being employed in treatment-resistant schizophrenia prior to clozapine. The conservative APP rate observed may have been influenced by an initiative within SLaM that reduced APP rates during the study window. Efforts to reduce the use of poorly evidenced prescribing should focus on adjuvant medications as well as APP.
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http://dx.doi.org/10.1177/0269881116632376DOI Listing
May 2016

New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.

Int J Epidemiol 2015 Oct;44(5):1706-21

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders.

Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born.

Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090).

Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.
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http://dx.doi.org/10.1093/ije/dyv136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881824PMC
October 2015

Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) traits in children and clinical ADHD.

J Am Acad Child Adolesc Psychiatry 2015 Apr 29;54(4):322-7. Epub 2015 Jan 29.

Medical Research Centre (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.

Objective: Twin studies and genome-wide complex trait analysis (GCTA) are not in agreement regarding heritability estimates for behavioral traits in children from the general population. This has sparked a debate on the possible difference in genetic architecture between behavioral traits and psychiatric disorders. In this study, we test whether polygenic risk scores associated with variation in attention-deficit/hyperactivity disorder (ADHD) trait levels in children from the general population predict ADHD diagnostic status and severity in an independent clinical sample.

Method: Single nucleotide polymorphisms (SNPs) with p < .5 from a genome-wide association study of ADHD traits in 4,546 children (mean age, 7 years 7 months) from the Avon Longitudinal Study of Parents and Children (ALSPAC; general population sample) were selected to calculate polygenic risk scores in 508 children with an ADHD diagnosis (independent clinical sample) and 5,081 control participants. Polygenic scores were tested for association with case-control status and severity of disorder in the clinical sample.

Results: Increased polygenic score for ADHD traits predicted ADHD case-control status (odds ratio = 1.17 [95% CI = 1.08-1.28], p = .0003), higher ADHD symptom severity (β = 0.29 [95% CI = 0.04-0.54], p = 0.02), and symptom domain severity in the clinical sample.

Conclusion: This study highlights the relevance of additive genetic variance in ADHD, and provides evidence that shared genetic factors contribute to both behavioral traits in the general population and psychiatric disorders at least in the case of ADHD.
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http://dx.doi.org/10.1016/j.jaac.2015.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382052PMC
April 2015

Neurocognitive abilities in the general population and composite genetic risk scores for attention-deficit hyperactivity disorder.

J Child Psychol Psychiatry 2015 Jun 3;56(6):648-56. Epub 2014 Oct 3.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Background: The genetic architecture of ADHD is complex, with rare and common variants involved. Common genetic variants (as indexed by a composite risk score) associated with clinical ADHD significantly predict ADHD and autistic-like behavioural traits in children from the general population, suggesting that ADHD lies at the extreme of normal trait variation. ADHD and other neurodevelopmental disorders share neurocognitive difficulties in several domains (e.g. impaired cognitive ability and executive functions). We hypothesised that ADHD composite genetic risk scores derived from clinical ADHD cases would also contribute to variation in neurocognitive abilities in the general population.

Methods: Children (N = 6,832) from a UK population cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), underwent neurocognitive testing. Parent-reported measures of their children's ADHD and autistic-like traits were used to construct a behavioural latent variable of 'neurodevelopmental traits'. Composite genetic risk scores for ADHD were calculated for ALSPAC children based on findings from an independent ADHD case-control genome-wide association study. Structural equation modelling was used to assess associations between ADHD composite genetic risk scores and IQ, working memory, inhibitory control and facial emotion recognition, as well as the latent 'neurodevelopmental trait' measure.

Results: The results confirmed that neurocognitive and neurodevelopmental traits are correlated in children in the general population. Composite genetic risk scores for ADHD were independently associated with lower IQ (β = -.05, p < .001) and working memory performance (β = -.034, p = .013), even after accounting for the relationship with latent neurodevelopmental behavioural trait scores. No associations were found between composite genetic risk scores and inhibitory control or emotion recognition (p > .05).

Conclusions: These findings suggest that common genetic variants relevant to clinically diagnosed ADHD have pleiotropic effects on neurocognitive traits as well as behavioural dimensions in the general population. This further suggests that the well-recognised association between cognition and neurodevelopmental behavioural traits is underpinned at a biological level.
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http://dx.doi.org/10.1111/jcpp.12336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431584PMC
June 2015

Common and rare variant analysis in early-onset bipolar disorder vulnerability.

PLoS One 2014 11;9(8):e104326. Epub 2014 Aug 11.

Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128749PMC
April 2015

Biological overlap of attention-deficit/hyperactivity disorder and autism spectrum disorder: evidence from copy number variants.

J Am Acad Child Adolesc Psychiatry 2014 Jul 21;53(7):761-70.e26. Epub 2014 Apr 21.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, UK.

Objective: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings.

Method: We compared copy number variant (CNV) data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. Using pathway analyses, we investigated whether CNVs observed in individuals with ADHD have an impact on genes in the same biological pathways as on those observed in individuals with ASD.

Results: The results suggest that the biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Moreover, this was true even when specific CNV regions common to both disorders were excluded from the analysis. After correction for multiple testing, genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample.

Conclusion: The results of this study indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions.
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http://dx.doi.org/10.1016/j.jaac.2014.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074351PMC
July 2014

Genetic risk for attention-deficit/hyperactivity disorder contributes to neurodevelopmental traits in the general population.

Biol Psychiatry 2014 Oct 25;76(8):664-71. Epub 2014 Feb 25.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff.

Background: Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population.

Methods: Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥ 1) ADHD item (n = 3623).

Results: Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥ 1 for ADHD traits, girls had a higher polygenic score than boys (p = .003).

Conclusions: These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD.
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http://dx.doi.org/10.1016/j.biopsych.2014.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183378PMC
October 2014

A population-based study of genetic variation and psychotic experiences in adolescents.

Schizophr Bull 2014 Nov 30;40(6):1254-62. Epub 2013 Oct 30.

Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK;

Psychotic experiences are not uncommon in general population samples, but no studies have examined to what extent confirmed risk variants for schizophrenia are associated with such experiences. A total of 3483 children in a birth cohort study participated in semistructured interviews for psychotic experiences at ages 12 and 18. We examined whether (1) a composite measure of risk for schizophrenia conferred by common alleles (polygenic score) was associated with psychotic experiences, (2) variants with genome-wide evidence for association with schizophrenia were associated with psychotic experiences, and (3) we could identify genetic variants for psychotic experiences using a genome-wide association (GWA) approach. We found no evidence that a schizophrenia polygenic score, or variants showing genome-wide evidence of association with schizophrenia, were associated with adolescent psychotic experiences within the general population. In fact, individuals who had a higher number of risk alleles for genome-wide hits for schizophrenia showed a decreased risk of psychotic experiences. In the GWA study, no variants showed GWA for psychotic experiences, and there was no evidence that the strongest hits (P < 5 × 10(-5)) were enriched for variants associated with schizophrenia in large consortia. Although polygenic scores are weak tools for prediction of schizophrenia, they show strong evidence of association with this disorder. Our findings, however, lend little support to the hypothesis that psychotic experiences in population-based samples of adolescents share a comparable genetic architecture to schizophrenia, or that utilizing a broader and more common phenotype of psychotic experiences will be an efficient approach to increase understanding of the genetic etiology of schizophrenia.
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http://dx.doi.org/10.1093/schbul/sbt146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193688PMC
November 2014

Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

Nat Genet 2013 Oct 25;45(10):1150-9. Epub 2013 Aug 25.

1] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3].

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
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http://dx.doi.org/10.1038/ng.2742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827979PMC
October 2013

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Nat Genet 2013 Sep 11;45(9):984-94. Epub 2013 Aug 11.

The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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http://dx.doi.org/10.1038/ng.2711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800159PMC
September 2013

Factor structure of autistic traits in children with ADHD.

J Autism Dev Disord 2014 Jan;44(1):204-15

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK,

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur. Factor analyses of ASD traits in children with and without ASD indicate the presence of social and restrictive-repetitive behaviour (RRB) factors. This study used exploratory factor analyses to determine the structure of ASD traits (assessed using the Social Communication Questionnaire) in children with ADHD. Distinct factors were observed for 'social' and 'rigidity' traits, corresponding to previous factor analyses in clinical ASD and population samples. This indicates that the split between social-communicative and RRB dimensions is unaffected by ADHD in children. Moreover, the study also finds that there is some overlap across hyperactive-impulsive symptoms and RRB traits in children with ADHD, which merits further investigation.
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http://dx.doi.org/10.1007/s10803-013-1865-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898364PMC
January 2014

Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia.

Br J Psychiatry 2013 Aug 23;203(2):107-11. Epub 2013 May 23.

Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.

Background: There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.

Aims: To determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.

Method: We used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.

Results: Schizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 10(-4), R(2) = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 × 10(-6), R(2) = 0.59%).

Conclusions: This increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.
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http://dx.doi.org/10.1192/bjp.bp.112.117432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730114PMC
August 2013

Autistic traits in children with ADHD index clinical and cognitive problems.

Eur Child Adolesc Psychiatry 2014 Jan 25;23(1):23-34. Epub 2013 Apr 25.

Child and Adolescent Psychiatry Section, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK,

Traits of autistic spectrum disorders (ASD) occur frequently in attention deficit hyperactivity disorder (ADHD), but the significance of their presence in terms of phenotype and underlying neurobiology is not properly understood. This analysis aimed to determine whether higher levels of autistic traits, as measured by the Social Communication Questionnaire (SCQ), index a more severe presentation in a large, rigorously phenotyped sample of children with ADHD (N=711). Regression analyses were used to examine association of SCQ scores with core ADHD features, clinical comorbidities and cognitive and developmental features, with adjustment for putative confounders. For outcomes showing association with total SCQ score, secondary analyses determined levels of differential association of the three ASD sub-domains. Results suggest that increasing ASD symptomatology within ADHD is associated with a more severe phenotype in terms of oppositional, conduct and anxiety symptoms, lower full-scale IQ, working memory deficits and general motor problems. These associations persisted after accounting for ADHD severity, suggesting that autistic symptomatology independently indexes the severity of comorbid impairments in the context of ADHD. Sub-domain scores did not show unique contributions to most outcomes, except that social deficits were independently associated with oppositional symptoms and repetitive behaviours independently predicted hyperactive-impulsive symptoms and motor problems. It would be worthwhile for clinicians to consider levels of socio-communicative and repetitive traits in those with ADHD who do not meet diagnostic criteria for ASD, as they index higher levels of phenotypic complexity, which may have implications for efficacy of interventions.
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http://dx.doi.org/10.1007/s00787-013-0398-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899449PMC
January 2014

High loading of polygenic risk for ADHD in children with comorbid aggression.

Am J Psychiatry 2013 Aug;170(8):909-16

MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.
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http://dx.doi.org/10.1176/appi.ajp.2013.12081129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935265PMC
August 2013

Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD.

Am J Psychiatry 2012 Feb;169(2):186-94

MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, Wales.

Objective: A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs.

Method: The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD.

Results: No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS.

Conclusions: Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601404PMC
http://dx.doi.org/10.1176/appi.ajp.2011.11040551DOI Listing
February 2012

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

J Alzheimers Dis 2012 ;28(2):377-87

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
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http://dx.doi.org/10.3233/JAD-2011-110824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118466PMC
May 2012

Phenotype evaluation and genomewide linkage study of clinical variables in schizophrenia.

Am J Med Genet B Neuropsychiatr Genet 2011 Dec 29;156B(8):929-40. Epub 2011 Sep 29.

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.

Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.
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http://dx.doi.org/10.1002/ajmg.b.31240DOI Listing
December 2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Nat Genet 2011 May 3;43(5):429-35. Epub 2011 Apr 3.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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http://dx.doi.org/10.1038/ng.803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084173PMC
May 2011