THE GENETIC ETIOLOGY OF ADHD

OBJECTIVES • To define ADHD • To present the science about the “popular theories” of ADHD pathogenesis • To talk about the well-defined, genetic portion of the basis for ADHD

DSM IV: ATTENTION DEFICIT HYPERACTIVITY DISORDER OR Inattentive • Difficulty sustaining attention • Lack of attention to detail • Difficulty organizing tasks • Avoidance of tasks that require concentration • Forgetfulness, losing things

Hyperactive-Impulsive

• Fidgeting • Moving excessively and inappropriately • Excessive talking • Blurting out, interrupting, intruding

AND

Impairment in function before age 7, in two or more settings

POPULAR THEORIES • Food additives (artificial colors, artificial flavors, preservatives) • 1970s, FDA statement in March 2011 • 2012 Meta-analysis of restriction diet studies1

• Refined sugar intake • Allergy vs. “Functional reactive hypoglycemia” • Sugar challenges, sugar restriction • 1995 and 2005 reviews2,3

1. Nigg JT, Lewis K, Edinger T, Falk M. Meta-analysis of attention-deficit/hyperactivity disorder or attentiondeficit/hyperactivity disorder symptoms, restriction diet, and synthetic food color additives. J Am Acad Child Adolesc Psychiatry. 2012;51(1):86. 2. Wolraich ML, Wilson DB, White JW. The effect of sugar on behavior or cognition in children. A meta-analysis. JAMA. 1995;274(20):1617. 3. Rojas NL, Chan E. Old and new controversies in the alternative treatment of attention-deficit hyperactivity disorder. Ment Retard Dev Disabil Res Rev. 2005;11(2):116

POPULAR THEORIES • Food allergen intolerance3 • Essential fatty acid deficiency4,5 • Iron deficiency • abnormal dopaminergic transmission • decreased ferritin = increased ADHD symptoms6 • Follow-up RCT7: supplementation helps!

3. Rojas NL, Chan E. Old and new controversies in the alternative treatment of attention-deficit hyperactivity disorder. Ment Retard Dev Disabil Res Rev. 2005;11(2):116 4. Gillies D, Sinn JKh, Lad SS, Leach MJ, Ross MJ. Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev. 2012;7:CD007986. 5. Bloch MH, Qawasmi A. Omega-3 fatty acid supplementation for the treatment of children with attentiondeficit/hyperactivity disorder symptomatology: systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2011 Oct;50(10):991-1000. Epub 2011 Aug 12. 6. Konofal E, Lecendreux M, Arnulf I, Mouren MC. Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 2004;158(12):1113. 7. Konofal E, Lecendreux M, Deron J, Marchand M, Cortese S, Zaïm M, Mouren MC, Arnulf I. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol. 2008;38(1):20.

NEUROTRANSMITTERS

EARLY STUDIES8 • Families, adoption, monozygotic twins • 2-8 fold risk increase between generations • 76% heritability between twins

• GWAS • 3 studies of 150-200 patients • regions implicated were different

• Case control and genetic family studies • Candidate genes chosen based on neurobiological theory

8. Stephen V. Faraonea, Roy H. Perlisb, Alysa E. Doyleb, Jordan W. Smollerb, Jennifer J. Goralnickc, Meredith A. Holmgrenc, Pamela Sklarb. Molecular Genetics of Attention-Deficit/Hyperactivity Disorder. Biol Psych Volume 57, Issue 11, 1 June 2005, Pages 1313–1323

CANDIDATE GENES: D4 • Dopamine receptor 4 (DRD4) • Strongly agonized by dopamine and norepinephrine • Prevalent in the frontal-subcortical areas • One variant (DRD4-7) is known to cause a blunted response to dopamine8 • Case control studies: OR 1.45; CI 1.27–1.65 • Symptom based studies: inattention, SAD

• Other variants are also associated with ADHD • Same exon, different repeat numbers • What is the true risk allele?

8. Stephen V. Faraonea, Roy H. Perlisb, Alysa E. Doyleb, Jordan W. Smollerb, Jennifer J. Goralnickc, Meredith A. Holmgrenc, Pamela Sklarb. Molecular Genetics of Attention-Deficit/Hyperactivity Disorder. Biol Psych Volume 57, Issue 11, 1 June 2005, Pages 1313–1323

CANDIDATE GENES: DBH • Dopamine beta-hydroxylase is responsible for the conversion of dopamine in norepinephrine in nerve terminals. • Taq1 restriction site polymorphism in intron 5 • Association in symptom scores, especially combined type • OR: 1.33 ; 95% CI 1.11–1.59

• GT repeat polymorphism upstream of the transcription start site • Known to decrease serum levels of DBH • Not significantly more common in ADHD

8. Stephen V. Faraonea, Roy H. Perlisb, Alysa E. Doyleb, Jordan W. Smollerb, Jennifer J. Goralnickc, Meredith A. Holmgrenc, Pamela Sklarb. Molecular Genetics of Attention-Deficit/Hyperactivity Disorder. Biol Psych Volume 57, Issue 11, 1 June 2005, Pages 1313–1323

CANDIDATE GENES: HTR1B • A serotonin receptor • A single nucleotide difference (G861C) has been associated with ADHD • OR 1.44; 95% CI 1.14–1.83 • However, it took a large study for the results to become significant

8. Stephen V. Faraonea, Roy H. Perlisb, Alysa E. Doyleb, Jordan W. Smollerb, Jennifer J. Goralnickc, Meredith A. Holmgrenc, Pamela Sklarb. Molecular Genetics of Attention-Deficit/Hyperactivity Disorder. Biol Psych Volume 57, Issue 11, 1 June 2005, Pages 1313–1323

COPY NUMBER VARIATIONS • the rate of rare (less than 1%) CNVs >100 kb was 1.15 times higher in ADHD patients9 • Genes within these sections are associated with autism and schizophrenia

• duplications at 15q13.3 • Frequency: 0.6% in the population • OR 2.22; 95% CI 1.5–3.6 • CHRNA7 • subunit of the neuronal nicotinic acetylcholine receptor • mediates dopamine release 9. Williams NM, Franke B, Mick E, Anney RJ, Freitag CM, Gill M, Thapar A, O'Donovan MC, Owen MJ, Holmans P, Kent L, Middleton F, Zhang-James Y, Liu L, Meyer J, Nguyen TT, Romanos J, Romanos M, Seitz C, Renner TJ, Walitza S, Warnke A, Palmason H, Buitelaar J, Rommelse N, Vasquez AA, Hawi Z, Langley K, Sergeant J, Steinhausen HC, Roeyers H, Biederman J, Zaharieva I, Hakonarson H, Elia J, Lionel AC, Crosbie J, Marshall CR, Schachar R, Scherer SW, Todorov A, Smalley SL, Loo S, Nelson S, Shtir C, Asherson P, Reif A, Lesch KP, Faraone SV. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry. 2012 Feb;169(2):195-204.

SUMMARY • There is a lot of folklore about ADHD • Be aware of what alternative therapies your patients may be trying, and give them options.

• ADHD has a well-proven genetic basis. • Nevertheless, it is a result of many small effects. • Important for counseling parents

• There is an environmental component • Behavior improves with study enrollment, regardless of what arm a child is in. • ORs are never terribly high • Hope for behavioral interventions

IN THE FUTURE… • We are still very basic in our understanding of the etiology, and the disease seems to involve many genes in a minor way. • Difficult to reproduce in animal models • No targets for gene therapy, or rational drug design

• GWAS studies of better power • For significance, it may be necessary to restrict studies to certain populations before we can compare between them. • Copy number variations explain too few cases