Genome-wide association studies in ADHD

Attention-deficit/hyperactivity disorder, ADHD, is a common and highly heritable neuropsychiatric disorder that is seen in children and adults. Although heritability is estimated at around 76%, it has been hard to find genes underlying the disorder. ADHD is a multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions. Whole genome linkage analyses have not yet lead to the identification of genes for ADHD, and results of candidate gene-based association studies have been able to explain only a tiny part of the genetic contribution to disease, either. A novel way of performing hypothesis-free analysis of the genome suitable for the identification of disease risk genes of considerably smaller effect is the genome-wide association study (GWAS). So far, five GWAS have been performed on the diagnosis of ADHD and related phenotypes. Four of these are based on a sample set of 958 parent–child trio’s collected as part of the International Multicentre ADHD Genetics (IMAGE) study and genotyped with funds from the Genetic Association Information Network (GAIN). The other is a pooled GWAS including adult patients with ADHD and controls. None of the papers reports any associations that are formally genome-wide significant after correction for multiple testing. There is also very limited overlap between studies, apart from an association with CDH13, which is reported in three of the studies. Little evidence supports an important role for the ‘classic’ ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1. There is extensive overlap with findings from other psychiatric disorders. Though not genome-wide significant, findings from the individual studies converge to paint an interesting picture: whereas little evidence—as yet—points to a direct involvement of neurotransmitters (at least the classic dopaminergic, noradrenergic and serotonergic pathways) or regulators of neurotransmission, some suggestions are found for involvement of ‘new’ neurotransmission and cell–cell communication systems. A potential involvement of potassium channel subunits and regulators warrants further investigation. More basic processes also seem involved in ADHD, like cell division, adhesion (especially via cadherin and integrin systems), neuronal migration, and neuronal plasticity, as well as related transcription, cell polarity and extracellular matrix regulation, and cytoskeletal remodeling processes. In conclusion, the GWAS performed so far in ADHD, though far from conclusive, provide a first glimpse at genes for the disorder. Many more (much larger studies) will be needed. For this, collaboration between researchers as well as standardized protocols for phenotyping and DNA-collection will become increasingly important

The IMAGE project: methodological issues for the molecular genetic analysis of ADHD

The genetic mechanisms involved in attention deficit hyperactivity disorder (ADHD) are being studied with considerable success by several centres worldwide. These studies confirm prior hypotheses about the role of genetic variation within genes involved in the regulation of dopamine, norepinephrine and serotonin neurotransmission in susceptibility to ADHD. Despite the importance of these findings, uncertainties remain due to the very small effects sizes that are observed. We discuss possible reasons for why the true strength of the associations may have been underestimated in research to date, considering the effects of linkage disequilibrium, allelic heterogeneity, population differences and gene by environment interactions. With the identification of genes associated with ADHD, the goal of ADHD genetics is now shifting from gene discovery towards gene functionality – the study of intermediate phenotypes ('endophenotypes'). We discuss methodological issues relating to quantitative genetic data from twin and family studies on candidate endophenotypes and how such data can inform attempts to link molecular genetic data to cognitive, affective and motivational processes in ADHD. The International Multi-centre ADHD Gene (IMAGE) project exemplifies current collaborative research efforts on the genetics of ADHD. This European multi-site project is well placed to take advantage of the resources that are emerging following the sequencing of the human genome and the development of international resources for whole genome association analysis. As a result of IMAGE and other molecular genetic investigations of ADHD, we envisage a rapid increase in the number of identified genetic variants and the promise of identifying novel gene systems that we are not currently investigating, opening further doors in the study of gene functionality

Targeting alphas can make coyote control more effective and socially acceptable

Research at the UC Hopland Research and Extension Center (HREC) has improved our understanding of how to reduce sheep depredation while minimizing the impact on coyotes. Analysis of a 14-year data set of HREC coyote-control efforts found that sheep depredation losses were not correlated with the number of coyotes removed in any of three time scales analyzed (yearly, seasonally and monthly) during corresponding intervals for the next 2 years. Field research using radiotelemetry to track coyotes supported and explained this finding. For example, in 1995, dominant “alphas” from four territories were associated with 89% of 74 coyote-killed lambs; “betas” and transients were not associated with any of these kills. Relatively few coyotes were killing sheep, and these animals were difficult to capture by conventional methods at the time of year when depredation was highest. However, selective removal of only the problem alpha coyotes effectively reduced losses at HREC

Targeting alphas can make coyote control more effective and socially acceptable

Research at the UC Hopland Research and Extension Center (HREC) has improved our understanding of how to reduce sheep depredation while minimizing the impact on coyotes. Analysis of a 14-year data set of HREC coyote-control efforts found that sheep depredation losses were not correlated with the number of coyotes removed in any of three time scales analyzed (yearly, seasonally and monthly) during corresponding intervals for the next 2 years. Field research using radiotelemetry to track coyotes supported and explained this finding. For example, in 1995, dominant “alphas” from four territories were associated with 89% of 74 coyote-killed lambs; “betas” and transients were not associated with any of these kills. Relatively few coyotes were killing sheep, and these animals were difficult to capture by conventional methods at the time of year when depredation was highest. However, selective removal of only the problem alpha coyotes effectively reduced losses at HREC

Reply to : On powerful GWAS in admixed populations

Non peer reviewe

Ancestry: How researchers use it and what they mean by it

Background: Ancestry is often viewed as a more objective and less objectionable population descriptor than race or ethnicity. Perhaps reflecting this, usage of the term “ancestry” is rapidly growing in genetics research, with ancestry groups referenced in many situations. The appropriate usage of population descriptors in genetics research is an ongoing source of debate. Sound normative guidance should rest on an empirical understanding of current usage; in the case of ancestry, questions about how researchers use the concept, and what they mean by it, remain unanswered.Methods: Systematic literature analysis of 205 articles at least tangentially related to human health from diverse disciplines that use the concept of ancestry, and semi-structured interviews with 44 lead authors of some of those articles.Results: Ancestry is relied on to structure research questions and key methodological approaches. Yet researchers struggle to define it, and/or offer diverse definitions. For some ancestry is a genetic concept, but for many—including geneticists—ancestry is only tangentially related to genetics. For some interviewees, ancestry is explicitly equated to ethnicity; for others it is explicitly distanced from it. Ancestry is operationalized using multiple data types (including genetic variation and self-reported identities), though for a large fraction of articles (26%) it is impossible to tell which data types were used. Across the literature and interviews there is no consistent understanding of how ancestry relates to genetic concepts (including genetic ancestry and population structure), nor how these genetic concepts relate to each other. Beyond this conceptual confusion, practices related to summarizing patterns of genetic variation often rest on uninterrogated conventions. Continental labels are by far the most common type of label applied to ancestry groups. We observed many instances of slippage between reference to ancestry groups and racial groups.Conclusion: Ancestry is in practice a highly ambiguous concept, and far from an objective counterpart to race or ethnicity. It is not uniquely a “biological” construct, and it does not represent a “safe haven” for researchers seeking to avoid evoking race or ethnicity in their work. Distinguishing genetic ancestry from ancestry more broadly will be a necessary part of providing conceptual clarity

Whole Genome Sequencing in Psychiatric Disorders: the WGSPD Consortium

As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls

SAIGE-GENE plus improves the efficiency and accuracy of set-based rare variant association tests

Several biobanks, including UK Biobank (UKBB), are generating large-scale sequencing data. An existing method, SAIGE-GENE, performs well when testing variants with minor allele frequency (MAF) SAIGE-GENE+ performs set-based rare variant association tests with improved type 1 error control and computational efficiency by collapsing ultra-rare variants and conducting multiple tests corresponding to different minor allele frequency cutoffs and annotations.Peer reviewe

Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides

Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5' and 3' splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the two "essential" splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combinations. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript, compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the "splice region" and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies.Peer reviewe