Genetics for
Mental Health Professionals
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ADHD: What Is It?
Attention deficit hyperactivity disorder (ADHD) is a condition that robs children of their ability to focus and pay attention. Kids with ADHD are fidgety and easily distracted. This makes it difficult to stay "on task," whether it's listening to a teacher or finishing a chore. A recent national study reported by the CDC noted that 11% of school aged children are being diagnosed with ADHD. The National Institute of Mental Health estimates 3% to 5% of kids have ADHD, but some experts believe that figure could be as high as 10%.
Brain Activity of ADHD
Children with ADHD have less activity in areas of the brain that control attention. They may also have imbalances in brain chemicals called neurotransmitters. It's unclear what causes these irregularities, but ADHD runs in families, so many experts believe genetics play a role
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ADHD Study examines DRD4
Evidence from twin, adoption, and family studies provide support for a genetic contribution to the etiology of ADHD
Several gene studies have identified an association between a 7-repeat variant in exon 3 of the dopamine 4 receptor gene (DRD4) and ADHD
In 2000, McCracken et al study’s Results showed a significant preferential transmission of the 240-bp (long) allele with ADHD. Exploratory analyses of the Inattentive phenotypic subtype of ADHD strengthened the evidence for linkage.
This data added further support for the role of DRD4 variants conferring increased risk for ADHD
McCracken, J. T., Smalley, S. L., McGough, J. J., Crawford, L. L., Del'Homme, M. M., Cantor, R. M., & ... Nelson, S. F. (2000). Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD). Molecular Psychiatry, 5(5), 531.
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ADHD Study examines SNAP-25
Mills et all in 2004 investigated the evidence suggesting a role for SNAP-25 (synaptosomal-associated protein of 25 kDa) in the genetic etiology of ADHD and found:
- Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting
- Overall our data provide some evidence for a role of this gene in ADHD
Mill, J. J., Richards, S. S., Knight, J. J., Curran, S. S., Taylor, E. E., & Asherson, P. P. (2004). Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD. Molecular Psychiatry, 9(8), 801-810. doi:10.1038/sj.mp.4001482
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ADHD Study examine Multiple Gene Pools
Yeh et al in 2004 identified current targets for etiology of ADHD:
- Dopamine receptor D4
- Solute carrier family 6, member 3
- Dopamine receptor D5
- Multigenic and genome scan approaches (the association between ADHD and 20 genes, including those from dopamine, serotonin, and adrenergic pathways)
Yeh, M., Morley, K. I., & Hall, W. D. (2004). The policy and ethical implications of genetic research on attention deficit hyperactivity disorder. Australian & New Zealand Journal Of Psychiatry, 38(1/2), 10-19. doi:10.1111/j.1440-1614.2004.01292.x
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ADHD Study examined Use of Phenotypic Correlations
In 2011, Grevan et al, identified that heritabilities were high, around 70% for ADHD symptoms and 45-65% for the reading measures
- Some of the same genes affected combined ADHD and reading with a genetic correlation of -.31
- Most notable finding was that the genetic correlation with reading was significantly greater for inattentiveness (-.31) than for hyperactivity-impulsivity (-.16), suggesting that genetic overlap between combined ADHD and reading is largely driven by inattentiveness
- Results showed that it is word decoding rather than reading comprehension that is differentially related to the ADHD dimensions (lower genetic correlation to hyperactivity-impulsivity than to inattentiveness)
Conclusion: Genetic overlap between ADHD and reading is largely driven by inattentiveness rather than hyperactivity-impulsivity.
Greven, C. U., Harlaar, N., Dale, P. S., & Plomin, R. (2011). Genetic overlap between ADHD symptoms and reading is largely driven by inattentiveness rather than hyperactivity-impulsivity. Journal Of The Canadian Academy Of Child & Adolescent Psychiatry, 20(1), 6-14.
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ADHD Study examined Gβ5-RGS Complexes
Xie et al in 2012 researched the disruption of monoamine neurotransmitter signaling through G protein-coupled receptors (GPCR) is considered to be a major contributing factor to the etiology of the ADHD
They concluded that: Genetic association evidence and functional data suggest that regulators of G protein signaling proteins of the R7 family (R7 RGS) that form obligatory complexes with type 5 G protein beta subunit (Gβ5) and negatively regulate signaling downstream from monoamine GPCRs may play a role in controlling hyperactivity.
Xie, K., Ge, S., Collins, V., Haynes, C., Renner, K., Meisel, R., & ... Martemyanov, K. (2012). Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems. Psychopharmacology, 219(3), 823-834. doi:10.1007/s00213-011-2409-y
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ADHD Study examined 14 Noradrenergic Genes
Hawi et all reported in 2013 that haplotype analyses demonstrated a significant association between ADHD and a SLC6A2 haplotype comprising the markers rs36009, rs1800887, rs8049681, rs2242447 and rs9930182 (χ209.39, p-corrected00.019, OR01.51)
A rare ADRA1B haplotype made of six SNPs (rs2030373, rs6884105, rs756275, rs6892282, rs6888306 and rs13162302) was also associated (χ207.79, p-corrected00.042 OR02.74) with the disorder
These findings provide evidence of a contribution of the noradrenaline system to the genetic etiology of ADHD
The observed haplotype association signals may be driven by as yet unidentified functional risk variants in or around the associated regions. Functional genomic analysis is warranted to determine the biological mechanism of the observed association.
Hawi, Z., Matthews, N., Barry, E., Kirley, A., Wagner, J., Wallace, R., & ... Bellgrove, M. (2013). A high density linkage disequilibrium mapping in 14 noradrenergic genes: Evidence of association between S LC6A2, ADRA1B and ADHD. Psychopharmacology, 225(4), 895-902. doi:10.1007/s00213-012-2875-x
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ADHD Study examined Twin Studies
Langer et al study in 2013 clearly reproduced the well-known strong genetic component in the etiology of ADHD
ADHD cases were identified by hospital or ambulatory ICD-10 diagnoses (F90.0 or F90.1) and prescriptions. We estimated tetrachoric correlations, percentage of concordant pairs, concordance rates, and heritability. Weighted estimates for the indirect assessment of mono- and dizygotic pairs were derived
Langner, I., Garbe, E., Banaschewski, T., & Mikolajczyk, R. T. (2013). Twin and sibling studies using health insurance data: The example of Attention Deficit/Hyperactivity Disorder (ADHD). Plos ONE, 8(4), 1-8. doi:10.1371/journal.pone.0062177
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ADHD GENETIC STUDY REFERENCES
Greven, C. U., Harlaar, N., Dale, P. S., & Plomin, R. (2011). Genetic overlap between
ADHD symptoms and reading is largely driven by inattentiveness rather than hyperactivity-impulsivity. Journal Of The Canadian Academy Of Child & Adolescent Psychiatry, 20(1), 6-14.
Hawi, Z., Matthews, N., Barry, E., Kirley, A., Wagner, J., Wallace, R., & ... Bellgrove, M.
(2013). A high density linkage disequilibrium mapping in 14 noradrenergic genes: Evidence of association between S LC6A2, ADRA1B and ADHD. Psychopharmacology, 225(4), 895-902. doi:10.1007/s00213-012-2875-x
Langner, I., Garbe, E., Banaschewski, T., & Mikolajczyk, R. T. (2013). Twin and sibling
studies using health insurance data: The example of Attention Deficit/Hyperactivity Disorder (ADHD). Plos ONE, 8(4), 1-8. doi:10.1371/journal.pone.0062177
McCracken, J. T., Smalley, S. L., McGough, J. J., Crawford, L. L., Del'Homme, M. M.,
Cantor, R. M., & ... Nelson, S. F. (2000). Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD). Molecular Psychiatry, 5(5), 531.
Mill, J. J., Richards, S. S., Knight, J. J., Curran, S. S., Taylor, E. E., & Asherson, P. P.
(2004). Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD. Molecular Psychiatry, 9(8), 801-810. doi:10.1038/sj.mp.4001482
Xie, K., Ge, S., Collins, V., Haynes, C., Renner, K., Meisel, R., & ... Martemyanov, K.
(2012). Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems. Psychopharmacology, 219(3), 823-834. doi:10.1007/s00213-011-2409-y
Yeh, M., Morley, K. I., & Hall, W. D. (2004). The policy and ethical implications of
genetic research on attention deficit hyperactivity disorder. Australian & New Zealand Journal Of Psychiatry, 38(1/2), 10-19. doi:10.1111/j.1440-1614.2004.01292.x
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