Jan K. Buitelaar

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

BACKGROUND: Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. METHODS: We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. FINDINGS: SNPs at four loci surpassed the cutoff for genome-wide significance (p<5x10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. INTERPRETATION: Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. FUNDING: National Institute of Mental Health.BACKGROUND Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. METHODS We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. FINDINGS SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. INTERPRETATION Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. FUNDING National Institute of Mental Health.

Prenatal maternal stress: effects on pregnancy and the (unborn) child

BACKGROUND Animal experiments have convincingly demonstrated that prenatal maternal stress affects pregnancy outcome and results in early programming of brain functions with permanent changes in neuroendocrine regulation and behaviour in offspring. AIM To evaluate the existing evidence of comparable effects of prenatal stress on human pregnancy and child development. STUDY DESIGN Data sources used included a computerized literature search of PUBMED (1966-2001); Psychlit (1987-2001); and manual search of bibliographies of pertinent articles. RESULTS Recent well-controlled human studies indicate that pregnant women with high stress and anxiety levels are at increased risk for spontaneous abortion and preterm labour and for having a malformed or growth-retarded baby (reduced head circumference in particular). Evidence of long-term functional disorders after prenatal exposure to stress is limited, but retrospective studies and two prospective studies support the possibility of such effects. A comprehensive model of putative interrelationships between maternal, placental, and fetal factors is presented. CONCLUSIONS Apart from the well-known negative effects of biomedical risks, maternal psychological factors may significantly contribute to pregnancy complications and unfavourable development of the (unborn) child. These problems might be reduced by specific stress reduction in high anxious pregnant women, although much more research is needed.

European clinical guidelines for hyperkinetic disorder -- first upgrade.

AbstractBackgroundThe validity of clinical guidelines changes over time, because new evidencebased knowledge and experience develop.ObjectiveHence, the European clinical guidelines on hyperkinetic disorder from 1998 had to be evaluated and modified.MethodDiscussions at the European Network for Hyperkinetic Disorders (EUNETHYDIS) and iterative critique of each clinical analysis. Guided by evidence-based information and based on evaluation (rather than metaanalysis) of the scientific evidence a group of child psychiatrists and psychologists from several European countries updated the guidelines of 1998. When reliable information is lacking the group gives a clinical consensus when it could be found among themselves.ResultsThe group presents here a set of recommendations for the conceptualisation and management of hyperkinetic disorder and attention deficit/hyperactivity disorder (ADHD).ConclusionA general scheme for practice in Europe could be provided, on behalf of the European Society for Child and Adolescent Psychiatry (ESCAP).

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder : association signals in DRD4, DAT1 and 16 other genes

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

Internal and external validity of Attention-Deficit Hyperactivity Disorder in a population-based sample of adults

BACKGROUND Follow-up studies of childhood ADHD have shown persistence of the disorder into adulthood, but no epidemiological data are yet available. METHOD ADHD DSM-IV symptoms were obtained by self-report in an adult population-based sample of 1813 adults (aged 18-75 years), that was drawn from an automated general practitioner system used in Nijmegen, The Netherlands. The structure of ADHD symptoms was analysed by means of confirmatory factor analyses. Other data used in this report are the General Health Questionnaire (GHQ-28), information about the presence of three core symptoms of ADHD in childhood, and about current psychosocial impairment. RESULTS The three-factor model that allowed for cross-loadings provided the best fit in the entire sample. This result was replicated across gender and age subsamples. Inattentive and hyperactivity symptom scores were significantly associated with measures of impairment, even after controlling for the GHQ-28. Subjects with four or more inattentive or hyperactive-impulsive symptoms were significantly more impaired than subjects with two, one and no symptoms. The prevalence of ADHD in adults was 1.0% (95% CI 0.6-1.6) and 2.5% (1.9-3.4) using a cutoff of six and four current symptoms respectively, and requiring the presence of all three core symptoms in childhood. CONCLUSIONS These results support the internal and external validity of ADHD in adults between 18 and 75 years. ADHD is not merely a child psychiatric disorder that persists into young adulthood, but an important and unique manifestation of psychopathology across the lifespan.

Executive Functioning in Adult ADHD: A Meta-Analytic Review

BACKGROUND Several theoretical explanations of ADHD in children have focused on executive functioning as the main explanatory neuropsychological domain for the disorder. In order to establish if these theoretical accounts are supported by research data for adults with ADHD, we compared neuropsychological executive functioning and non-executive functioning between adults with ADHD and normal controls in a meta-analytic design. METHOD We compared 13 studies that (1) included at least one executive functioning measure, (2) compared the performance of an adult ADHD group with that of an adult normal control group, (3) provided sufficient information for calculation of effect sizes, and (4) used DSM-III-R or DSM-IV criteria to diagnose ADHD. RESULTS We found medium effect sizes both in executive functioning areas [verbal fluency (d= 0-62), inhibition (d = 0-64 and d = 0.89), and set shifting (d = 0.65)] and in non-executive functioning domains [consistency of response (d = 0.57), word reading (d = 0.60) and color naming (d = 0.62)]. CONCLUSIONS Neuropsychological difficulties in adult ADHD may not be confined to executive functioning. The field is in urgent need of better-designed executive functioning tests, methodological improvements, and direct comparisons with multiple clinical groups to answer questions of specificity.

Anatomical MRI of the developing human brain: what have we learned?

OBJECTIVE To critically review and integrate the existing literature on magnetic resonance imaging (MRI) studies of the normally developing brain in childhood and adolescence and discuss the implications for clinical MRI studies. METHOD Changes in regional brain volume with age and differences between the sexes are summarized from reports in refereed journal articles pertaining to MRI of the developing human brain. RESULTS White matter volume increases with age. Gray matter volumes increase during childhood and then decrease before adulthood. On average, boys have larger brains than girls; after correction for overall brain volume the caudate is relatively larger in girls, and the amygdala is relatively larger in boys. Differences are of clinical interest given gender-related differences in the age of onset, symptomatology, and prevalence noted for nearly all childhood-onset psychiatric disorders. Attention-deficit/hyperactivity disorder is frequently used as an example to demonstrate these points. CONCLUSIONS Understanding the developmental trajectories of normal brain development and differences between the sexes is important for the interpretation of clinical imaging studies.

Long-acting medications for the hyperkinetic disorders : A systematic review and European treatment guideline

A systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorder is reported, giving effect sizes and numbers-to-treat for extended-release stimulant preparations and atomoxetine (ATX). A panel of experts from several European countries used the review to make recommendations about the use of these drugs in practice, and conclusions are reported: (1) Long-acting preparations should be available and used; (2) They should not replace short-acting drugs (which will be the initial treatment for many children for reasons of cost and flexibility of dosing). Individual clinical choice is needed. (3) Both ATX and extended-release preparations of stimulants should be available. The choice will depend upon the circumstances, and detailed recommendations are made.

Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes. However, genetic association studies of the BDNF Val66Met polymorphism (single nucleotide polymorphism rs6265) in major depressive disorder (MDD) have produced inconsistent results. We conducted a meta-analysis of studies comparing the frequency of the BDNF Val66Met-coding variant in depressed cases (MDD) and nondepressed controls. A total of 14 studies involving 2812 cases with DSM-III or -IV defined MDD and 10 843 nondepressed controls met the inclusion criteria. Analyses were stratified either by gender or ethnicity (Asian and Caucasian) because MDD is more prevalent in women and in Caucasians and because BDNF allele frequencies differ by ethnicity. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were provided for allelic analyses (Met versus Val), as well as for genotypic analyses (Met/Met and Val/Met versus Val/Val). In the total sample, the BDNF Val66Met polymorphism was not significantly associated with depression. However, the gender stratified analyses revealed significant effects in both the allelic and genotypic analyses in men (ORMET, 95% CI; 1.27 (1.10–1.47); ORMET/MET, 95% CI; 1.67 (1.19–2.36)). Stratification according to ethnicity did not show significant effects of the Val66Met polymorphism on MDD. Our results suggest that the BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women. Future research into gender issues will be of interest.

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder

OBJECTIVE Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. METHOD We used data from four projects: a) the Childrens Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. RESULTS No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. CONCLUSIONS Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorders heritability.