Study Identifies Possible Genetic Origin for ADHD

Children with attention deficit/hyperactivity disorder (ADHD) have more large genetic variations than controls, according to British and Icelandic researchers. In addition, the affected genes are located in regions with known connections to autism and schizophrenia.

The genomewide association study for the first time establishes a genetic basis for ADHD, wrote Nigel Williams, Ph.D., Anita Thapar, M.D., and co-authors in the September 30 issue of The Lancet.

Williams is a senior lecturer and Thapar is a professor of child and adolescent psychiatry at the MRC Centre for Neuropsychiatric Genetics and Genomics and MRC Centre for Neuropsychiatric Genetics at Cardiff University School of Medicine in Cardiff, Wales.

“Too often, people dismiss ADHD as being due to bad parenting or poor diet,” said Thapar in a statement. “Now we can say with confidence that ADHD is a genetic disease and that the brains of children with this condition develop differently from those of other children.”

“This study adds more good evidence to the already strong evidence of a biological basis of ADHD,” Philip Shaw, M.D., Ph.D., a staff clinician at the National Institute of Mental Health in Bethesda, Md., who was not involved in the new research, told Psychiatric News.

ADHD is a highly heritable psychiatric disorder, but previous genomewide association and linkage studies found few common risk variants, wrote Williams and Thapar.

Earlier work was based on copy number variants (CNVs) of all sizes, but the new study examined only larger CNVs, they said.

Copy number variants are duplications or deletions in the genome.

The researchers compared data on single nucleotide polymorphisms from 366 children in the United Kingdom who met DSM-IV criteria for ADHD with data from 1,047 controls.

Children with ADHD had “a highly significant excess of large, rare CNVs” compared with controls. In fact, 14 percent of children with ADHD carried a CNV larger than 500 kb, versus 7 percent among controls.

The frequency of these large, rare CNVs was highest among children with both ADHD and intellectual disability. However, even among the 319 children without intellectual disability, large CNVs were 1.68 times more common. In those children, eight of 40 large (>500 kb) CNVs overlapped a locus for autism. Only 1 in 78 of large CNVs in the controls fell into that locus.

The excess CNVs in the children with ADHD occurred largely on chromosome 16p13.11, an observation replicated on a separate Icelandic dataset of 825 ADHD patients and 35,243 controls.

Prior research has found that deletions in this region were strongly associated with intellectual disability, wrote Williams and colleagues. “Duplications have been detected in patients with autism, intellectual disability, and schizophrenia, again suggesting that the same large, rare CNVs might contribute to several, phenotypically different neurodevelopmental disorders.”

One particular gene on 16p13.11, NDE1, plays a role in neurodevelopment and interacts with DISC1, a gene that has been intensively studied for its association with schizophrenia and other mental disorders.

“Our results suggest that routine referral to clinical geneticists and screening for such mutations could be helpful for children with ADHD and intellectual disability,” wrote the authors.

Others may think that it is too early to take the research into the clinic yet, given the existing ability of clinical assessments to diagnose the condition. However, the study may open a door to a better understanding of the origins of ADHD.

“This should be a fruitful area of research in ADHD,” said Paul Ballas, D.O., M.S., inhouse psychiatrist at the Greentree School Clinic, an attending psychiatrist at Friends Hospital in Philadelphia, and a spokesperson for the American Academy of Child and Adolescent Psychiatry.

“Maybe more funding will become available to look more closely at this chromosome,” said Ballas. “Hopefully, we can get closer to the specific cluster of genes involved in ADHD.”

While the study must be replicated, future research may illuminate the biology of these genes and characterize their action in humans, said Shaw.

An abstract of “Rare Chromosomal Deletions and Duplications in Attention-Deficit Hyperactivity Disorder: A Genome-Wide Analysis” is posted at <www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61109-9/abstract>.