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CIDR-Whole Genome Sequencing: Prospective Birth Cohort to Elucidate Etiology of ADHD in US Minority Children

Attention Deficit Hyperactivity Disorder (ADHD) is the most common pediatric developmental disability, affecting at least 6 million U.S. children; children from minority racial and ethnic populations, such as Black children, are at even higher risk. A major challenge in preventing and treating ADHD is that the causes remain unclear. Available data suggest that both genetic and early life environmental factors may play a role. On the genetics forefront, although an increasing number of genome-wide association studies (GWAS) have been conducted, and many genetic variants have been linked to risk of ADHD, these loci only explain a small fraction of ADHD. One puzzle has been the substantial discrepancy in estimated heritability of ADHD by GWAS (10% to 28%) vs. family-based studies (~80%). This so called “missing heritability” could be due to limitations of available arrays for conducting GWAS. For example, loci identified by GWAS could simply be surrogates for causal variants and/or functional genes associated with ADHD, and important single nucleotide variations (SNVs) or genetic structural variants (SVs) are not captured by GWAS.

To advance the field, we integrated whole genome sequencing (WGS) with a well-established and well-phenotyped prospective Boston Birth Cohort (BBC) comprised of predominantly US, Black children from under-resourced urban settings. These children were enrolled at birth and followed up to age 21 years. We performed WGS for 500 Black children, about half with clinically diagnosed ADHD and another half neurotypical children. WGS offers an unprecedented opportunity to examine the entire genome, including rare SNVs (including insertion or deletions), SNVs in the noncoding region (a potentially large and hitherto unexplored class of variations), and SVs (including copy number variations) not captured by current arrays for GWAS. We anticipate that this study will enable us to gain deeper insight into the genetic architecture underlying the development of ADHD, its findings will be directly relevant to reduce the health disparity of ADHD in the United States.