[show abstract][hide abstract] ABSTRACT: Background
Attention-deficit hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies also suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD)/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.
Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N=8,229), 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 also ASD-related measures (pragmatic language abilities and social cognition) in ALSPAC. Polygenic scores were also compared in males and females endorsing any (≥1) ADHD item (N=3,623).
ADHD polygenic risk showed a positive association with ADHD (hyperactive-impulsive: p=0.0039; inattentive: p=0.037) traits. ADHD polygenic risk was also negatively associated with pragmatic language abilities (p=0.037), but not with social cognition (p=0.43). In children with a rating ≥1 for ADHD traits, females had a higher polygenic score than males (p=0.003).
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.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Autism and Developmental Disorders 06/2013; · 3.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10−157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10−9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10−8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10−10, odds ratio = 0.86; rs3851179, P = 1.3 × 10−9, odds ratio = 0.86).
[show abstract][hide abstract] ABSTRACT: 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.
The British journal of psychiatry: the journal of mental science 05/2013; · 6.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
European Child & Adolescent Psychiatry 04/2013; · 3.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
American Journal of Psychiatry 04/2013; · 14.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78–100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10(-3) from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10(-4)) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10(-9), odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10(-8), OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.Molecular Psychiatry advance online publication, 16 October 2012; doi:10.1038/mp.2012.142.
[show abstract][hide abstract] ABSTRACT: The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.Molecular Psychiatry advance online publication, 22 May 2012; doi:10.1038/mp.2012.67.
[show abstract][hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified a number of loci that have strong support for their association with bipolar disorder (BD). The Psychiatric Genome-Wide Association Study (GWAS) Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis of BD GWAS data sets and replication samples identified evidence (P=6.7 × 10(-7), odds ratio (OR)=1.147) of association with the risk of BD at the polymorphism rs9371601 within SYNE1, a gene which encodes nesprin-1. Here we have tested this polymorphism in an independent BD case (n=1527) and control (n=1579) samples, and find evidence for association (P=0.0095) with similar effect sizes to those previously observed in BD (allelic OR=1.148). In a combined (meta) analysis of PGC-BD data (both primary and replication data) and our independent BD samples, we found genome-wide significant evidence for association (P=2.9 × 10(-8), OR=1.104). We have also examined the polymorphism in our recurrent unipolar depression cases (n=1159) and control (n=2592) sample, and found that the risk allele was associated with risk for recurrent major depression (P=0.032, OR=1.118). Our findings add to the evidence that association at this locus influences susceptibility to bipolar and unipolar mood disorders.Molecular Psychiatry advance online publication, 8 May 2012; doi:10.1038/mp.2012.48.
[show abstract][hide abstract] ABSTRACT: Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.
We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.
In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.
The current evidence linking common mtDNA variations with AD is not compelling.
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.
American Journal of Psychiatry 02/2012; 169(2):186-94. · 14.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.