ebook_ADHD2019_engl.

The World Federation of ADHD Guide 5 determines if one version of that marker is more common in people with ADHD compared with people without ADHD. The marker is either a single DNA base pair known as a single nucleotide polymorphism (SNP) or a longer stretch of DNA made of several SNPs. The DNA variants used as markers usually have no func- tional significance. They are only used to locate the gene on the genome. When an association is positive, we can conclude that a causal DNA variant is located somewhere near the marker. In meta-analyses of candidate gene studies, Gizer et al., 8 found eight DNA va- riants to be associated with ADHD. These variants pointed to: the serotonin trans- porter gene ( 5HTT ), the dopamine transporter gene ( DAT1 ), the D4 dopamine receptor gene ( DRD4 ), the D5 dopamine receptor gene ( DRD5 ), the serotonin 1B receptor gene ( HTR1B ) and a gene coding for a synaptic vesicle regulating protein known as SNAP25 . A meta-analysis limited to studies of adults with ADHD found adult ADHD to be associated with BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), which regulates the growth of neurons. 9 Both meta-analy- ses found that although results reached statistical significance, the magnitude of association was small, as indicated by odds ratios less than 1.5. Considering that the human genome contains about 20,000 protein coding ge- nes along with regulatory regions that moderate the expression of these genes, candidate gene studies are remarkably limited in scope. To deal with that problem, the genome-wide association study (GWAS) was developed. GWAS assays DNA variants across the entire genome to provide information about the association of ADHD to any gene or regulatory element. Because this requires statistical tests of millions of SNPs, very large samples are required to achieve confident results. To achieve this goal for ADHD, a worldwide consortium of researchers banded together to collect a sample of 20,183 people with ADHD and 35,191 controls. 10 The study found that twelve loci on the genome were almost certain to harbor a DNA variant that increased the risk for ADHD. One of these loci is especially interesting because it implicates the FOXP2 gene. Variants in this gene are known to increase the risk for speech and language disorders. Many of the other loci discovered by the ADHD GWAS implicated genes that are expressed in brain and could putatively be involved in ADHD. None of them, however, were any of the candidate genes that had been studied in the 1990s. Among these, only SLC9A9 showed a weak association with ADHD. This gene encodes a protein that regulates the recycling of receptors and transporters to the synaptic membrane. Were the researchers in the 1990s wrong about the candidate genes they proposed? Possibly, but we know from GWAS of other psychiatric di- sorders that we will need very large samples (perhaps hundreds of thousands) to detect most of the DNA variants that increase the risk for ADHD. Perhaps the most important finding from the ADHD GWAS was the result from a complex statistical analysis that concluded ADHD must be a polygenic disorder. By ‘polygenic’ we mean that many, many DNA variants (10s or 100s of