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. ]]>
This study includes 500 children who met ADHD or neurotypical definition and whose mothers self-identified as Black, Haitian or Cap Verde, and who are enrolled in the Boston Birth Cohort.Inclusion criteria: Mothers who deliver singleton live births are eligible for the study. Exclusion criteria: Pregnancies as a result of in vitro fertilization or multiple gestations, fetal chromosomal abnormalities, or major birth defects are excluded. ]]>
The study sample is from the Boston Birth Cohort (BBC), one of the largest and longest minority birth cohorts in the U.S. for studying pregnancy and child health outcomes, funded continuously by the NIH for over 20 years. Recruitment of BBC participants has been ongoing since 1998 at the Boston Medical Center (BMC), a major tertiary hospital located in urban Boston. Mother-infant pairs are recruited 1-3 days after birth, with a participation rate over 90% among the mothers we approached.Data collection procedures: After obtaining written informed consent, mothers are interviewed by trained staff using a standardized questionnaire. Maternal and infant medical records are reviewed. Maternal blood and cord blood samples and placental tissues are collected using a standard protocol. Postnatal follow-up of the BBC has been ongoing since 2004, with a median length of 14 years. Postnatal follow up has focused on BBC children who chose BMC as their pediatric primary care site. Mothers are interviewed at scheduled study visits by trained staff using a standardized questionnaire to gather important postnatal nutrition and epidemiologic data and to obtain child blood samples. Electronic medical records (EMRs) of the study children are abstracted annually, including clinical measurements, ICD diagnosis codes, medications, and laboratory results. ]]>