Abstract
During the past 15 years, an impressive amount of genetic information has become available in the research field of psychiatry, particularly as it relates to attention-deficit/hyperactivity disorder (ADHD). However, the classical clinical approach to ADHD has minimally affected and not significantly been improved by this genetic revolution. It is difficult to predict how long it will take for genetic findings to alter the way clinicians treat patients with ADHD. New medications or treatment protocols may take years to become routine clinical practice. However, when taken together, recent successes in genomics, pharmacogenomics, and genetic epidemiology have the potential (1) to prevent comorbid consequences of ADHD, (2) to individualize therapies for patients with ADHD, and (3) to define new epidemiological policies to aid with the impact of ADHD on society. Here, we present an overview of how genetic research may affect and improve the quality of life of patients with ADHD: as an example, we use the discovery of LPHN3, a new gene in which variants have recently been shown to be associated with ADHD.
Similar content being viewed by others
References
Acosta MT, Arcos-Burgos M, Muenke M (2004) Attention deficit/hyperactivity disorder (ADHD): complex phenotype, simple genotype? Genet Med 6(1):1–15
Arcos-Burgos M, Acosta MT (2007) Tuning major gene variants conditioning human behavior: the anachronism of ADHD. Curr Opin Genet Dev 17(3):234–238
Arcos-Burgos M, Muenke M (2002) Genetics of population isolates. Clin Genet 61(4):233–247
Arcos-Burgos M, Castellanos FX, Lopera F, Pineda D, Palacio JD, Garcia M et al (2002) Attention-deficit/hyperactivity disorder (ADHD): feasibility of linkage analysis in a genetic isolate using extended and multigenerational pedigrees. Clin Genet 61(5):335–343
Arcos-Burgos M, Castellanos FX, Konecki D, Lopera F, Pineda D, Palacio JD et al (2004a) Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate. Mol Psychiatry 9(3):252–259
Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG et al (2004b) Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet 75(6):998–1014
Arcos-Burgos M, Jain M, Acosta MT, Shively S, Stanescu H, Wallis D et al. (2010) A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry (in press)
Banerjee E, Sinha S, Chatterjee A, Gangopadhyay PK, Singh M, Nandagopal K (2006) A family-based study of Indian subjects from Kolkata reveals allelic association of the serotonin transporter intron-2 (STin2) polymorphism and attention-deficit-hyperactivity disorder (ADHD). Am J Med Genet B Neuropsychiatr Genet 141B(4):361–366
Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C et al (1992) Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples. Arch Gen Psychiatry 49(9):728–738
Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N et al (2006) The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry 11(10):934–953
Cadieu E, Neff MW, Quignon P, Walsh K, Chase K, Parker HG et al (2009) Coat variation in the domestic dog is governed by variants in three genes. Science 326(5949):150–153
Carvajal-Carmona LG, Ophoff R, Service S, Hartiala J, Molina J, Leon P et al (2003) Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica. Hum Genet 112(5–6):534–541
Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P et al (2009) Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA 106(45):19096–19101
Coghill D, Banaschewski T (2009) The genetics of attention-deficit/hyperactivity disorder. Expert Rev Neurother 9(10):1547–1565
Collins FS, Manolio TA (2007) Merging and emerging cohorts: necessary but not sufficient. Nature 445(7125):259
Comings DE, Chen C, Wu S, Muhleman D (1999) Association of the androgen receptor gene (AR) with ADHD and conduct disorder. Neuroreport 10(7):1589–1592
Durrant C, Morris AP (2005) Linkage disequilibrium mapping via cladistic analysis of phase-unknown genotypes and inferred haplotypes in the Genetic Analysis Workshop 14 simulated data. BMC Genet 6(Suppl 1):S100
Durrant C, Zondervan KT, Cardon LR, Hunt S, Deloukas P, Morris AP (2004) Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes. Am J Hum Genet 75(1):35–43
Elia J, Capasso M, Zaheer Z, Lantieri F, Ambrosini P, Berrettini W et al (2009) Candidate gene analysis in an on-going genome-wide association study of attention-deficit hyperactivity disorder: suggestive association signals in ADRA1A. Psychiatr Genet 19(3):134–141
Elston RC, Yelverton KC (1975) General models for segregation analysis. Am J Hum Genet 27(1):31–45
Faraone SV, Mick E (2010) Molecular genetics of attention deficit hyperactivity disorder. Psychiatr Clin North Am 33(1):159–180
Faraone SV, Biederman J, Weiffenbach B, Keith T, Chu MP, Weaver A et al (1999) Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. Am J Psychiatry 156(5):768–770
Faraone SV, Biederman J, Monuteaux MC (2000) Toward guidelines for pedigree selection in genetic studies of attention deficit hyperactivity disorder. Genet Epidemiol 18(1):1–16
Faraone SV, Doyle AE, Mick E, Biederman J (2001) Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry 158(7):1052–1057
Franke B, Neale BM, Faraone SV (2009) Genome-wide association studies in ADHD. Hum Genet 126(1):13–50
Friedel S, Saar K, Sauer S, Dempfle A, Walitza S, Renner T et al (2007) Association and linkage of allelic variants of the dopamine transporter gene in ADHD. Mol Psychiatry 12(10):923–933
Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126(1):51–90
Guo X, Elston RC (2000) Two-stage global search designs for linkage analysis II: including discordant relative pairs in the study. Genet Epidemiol 18(2):111–127
Hildebrandt M, Bender R, Gehrmann U, Blettner M (2006) Calculating confidence intervals for impact numbers. BMC Med Res Methodol 6:32
Ichtchenko K, Khvotchev M, Kiyatkin N, Simpson L, Sugita S, Sudhof TC (1998) alpha-latrotoxin action probed with recombinant toxin: receptors recruit alpha-latrotoxin but do not transduce an exocytotic signal. EMBO J 17(21):6188–6199
Iyengar SK, Song D, Klein BE, Klein R, Schick JH, Humphrey J et al (2004) Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am J Hum Genet 74(1):20–39
Jain M, Palacio LG, Castellanos FX, Palacio JD, Pineda D, Restrepo MI et al (2007) Attention-deficit/hyperactivity disorder and comorbid disruptive behavior disorders: evidence of pleiotropy and new susceptibility loci. Biol Psychiatry 61(12):1329–1339
Kent L, Doerry U, Hardy E, Parmar R, Gingell K, Hawi Z et al (2002) Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis. Mol Psychiatry 7(8):908–912
Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N et al (2005) Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD. Mol Psychiatry 10(10):939–943
Kieling C, Goncalves RR, Tannock R, Castellanos FX (2008) Neurobiology of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 17(2):285–307, viii
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921
Ledford H (2010) Africa yields two full human genomes. Nature 463(7283):857
Lee SS, Lahey BB, Waldman I, Van Hulle CA, Rathouz P, Pelham WE et al (2007) Association of dopamine transporter genotype with disruptive behavior disorders in an eight-year longitudinal study of children and adolescents. Am J Med Genet B Neuropsychiatr Genet 144B(3):310–317
Lelianova VG, Davletov BA, Sterling A, Rahman MA, Grishin EV, Totty NF et al (1997) Alpha-latrotoxin receptor, latrophilin, is a novel member of the secretin family of G protein-coupled receptors. J Biol Chem 272(34):21504–21508
Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Roser C, Nguyen TT et al (2008) Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm 115(11):1573–1585
Li D, Sham PC, Owen MJ, He L (2006) Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 15(14):2276–2284
Linets’ka MV, Storchak LH, Himmelreich NH (2002) Effect of synaptosomal cytosolic [3H]GABA pool depletion on secretory ability of alpha-latrotoxin. Ukr Biokhim Zh 74(3):65–72
Lopera F, Palacio LG, Jimenez I, Villegas P, Puerta IC, Pineda D et al (1999) Discrimination between genetic factors in attention deficit. Rev Neurol 28(7):660–664
Lowe N, Kirley A, Hawi Z, Sham P, Wickham H, Kratochvil CJ et al (2004) Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes. Am J Hum Genet 74(2):348–356
Maher BS, Marazita ML, Moss HB, Vanyukov MM (1999) Segregation analysis of attention deficit hyperactivity disorder. Am J Med Genet 88(1):71–78
Maher BS, Marazita ML, Ferrell RE, Vanyukov MM (2002) Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Psychiatr Genet 12(4):207–215
Manolio TA, Collins FS (2009) The HapMap and genome-wide association studies in diagnosis and therapy. Annu Rev Med 60:443–456
Manolio TA, Rodriguez LL, Brooks L, Abecasis G, Ballinger D, Daly M et al (2007) New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat Genet 39(9):1045–1051
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ et al (2009) Finding the missing heritability of complex diseases. Nature 461(7265):747–753
Manor I, Tyano S, Mel E, Eisenberg J, Bachner-Melman R, Kotler M et al (2002) Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA). Mol Psychiatry 7(6):626–632
Marazita ML, Elston RC, Namboodiri KK, Hames CG (1983) Factors contributing to the variability in serum lipid levels and blood pressure in a large kindred. Am J Epidemiol 118(6):806–817
Marazita ML, Spence MA, Melnick M (1984) Genetic analysis of cleft lip with or without cleft palate in Danish kindreds. Am J Med Genet 19(1):9–18
Marazita ML, Spence MA, Melnick M (1986) Major gene determination of liability to cleft lip with or without cleft palate: a multiracial view. J Craniofac Genet Dev Biol Suppl 2:89–97
Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 67(1):146–154
Matsushita H, Lelianova VG, Ushkaryov YA (1999) The latrophilin family: multiply spliced G protein-coupled receptors with differential tissue distribution. FEBS Lett 443(3):348–352
Mee CJ, Tomlinson SR, Perestenko PV, De Pomerai D, Duce IR, Usherwood PN et al (2004) Latrophilin is required for toxicity of black widow spider venom in Caenorhabditis elegans. Biochem J 378(Pt 1):185–191
Neuman RJ, Heath A, Reich W, Bucholz KK, Madden PAF, Sun L et al (2001) Latent class analysis of ADHD and comorbid symptoms in a population sample of adolescent female twins. J Child Psychol Psychiatry 42(7):933–942
Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C et al (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461(7261):272–276
Palacio JD, Castellanos FX, Pineda DA, Lopera F, Arcos-Burgos M, Quiroz YT et al (2004) Attention-deficit/hyperactivity disorder and comorbidities in 18 Paisa Colombian multigenerational families. J Am Acad Child Adolesc Psychiatry 43(12):1506–1515
Pineda DA, Palacio LG, Puerta IC, Merchan V, Arango CP, Galvis AY et al (2007) Environmental influences that affect attention deficit/hyperactivity disorder: study of a genetic isolate. Eur Child Adolesc Psychiatry 16(5):337–346
Rasmussen ER, Neuman RJ, Heath AC, Levy F, Hay DA, Todd RD (2002) Replication of the latent class structure of attention-deficit/hyperactivity disorder (ADHD) subtypes in a sample of Australian twins. J Child Psychol Psychiatry 43(8):1018–1028
Reiersen AM, Constantino JN, Grimmer M, Martin NG, Todd RD (2008) Evidence for shared genetic influences on self-reported ADHD and autistic symptoms in young adult Australian twins. Twin Res Hum Genet 11(6):579–585
Ribases M, Ramos-Quiroga JA, Hervas A, Bosch R, Bielsa A, Gastaminza X et al (2009) Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB. Mol Psychiatry 14(1):71–85
Risch N (1990a) Linkage strategies for genetically complex traits. III. The effect of marker polymorphism on analysis of affected relative pairs. Am J Hum Genet 46(2):242–253
Risch N (1990b) Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet 46(2):229–241
Risch N (1990c) Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 46(2):222–228
Risch N (1990) Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol 7(1):3–16 (discussion 7–45)
Risch N, Merikangas KR (1993) Linkage studies of psychiatric disorders. Eur Arch Psychiatry Clin Neurosci 243(3–4):143–149
Risch N, Teng J (1998) The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases I. DNA pooling. Genome Res 8(12):1273–1288
Risch N, Zhang H (1995) Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science 268(5217):1584–1589
Schliekelman P, Slatkin M (2002) Multiplex relative risk and estimation of the number of loci underlying an inherited disease. Am J Hum Genet 71(6):1369–1385
Service S, DeYoung J, Karayiorgou M, Roos JL, Pretorious H, Bedoya G et al (2006) Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nat Genet 38(5):556–560
Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M et al (2005) Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Mol Psychiatry 10(10):944–949
Slatkin M (2008) Genotype-specific recurrence risks as indicators of the genetic architecture of complex diseases. Am J Hum Genet 83(1):120–126
Slatkin M (2009) Epigenetic inheritance and the missing heritability problem. Genetics 182(3):845–850
Smith AK, Mick E, Faraone SV (2009) Advances in genetic studies of attention-deficit/hyperactivity disorder. Curr Psychiatry Rep 11(2):143–148
Spencer TJ, Biederman J, Mick E (2007) Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. J Pediatr Psychol 32(6):631–642
Stricker C, Fernando RL, Elston RC (1995) Linkage analysis with an alternative formulation for the mixed model of inheritance: the finite polygenic mixed model. Genetics 141(4):1651–1656
Sugita S, Ichtchenko K, Khvotchev M, Sudhof TC (1998) alpha-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors G-protein coupling not required for triggering exocytosis. J Biol Chem 273(49):32715–32724
Thapar A, O’Donovan M, Owen MJ (2005) The genetics of attention deficit hyperactivity disorder. Hum Mol Genet 14 Spec No. 2:R275–R282
van den Oord EJ, Boomsma DI, Verhulst FC (1994) A study of problem behaviors in 10- to 15-year-old biologically related and unrelated international adoptees. Behav Genet 24(3):193–205
Waldman ID, Gizer IR (2006) The genetics of attention deficit hyperactivity disorder. Clin Psychol Rev 26(4):396–432
Willcutt EG, Pennington BF, Chhabildas NA, Friedman MC, Alexander J (1999) Psychiatric comorbidity associated with DSM-IV ADHD in a nonreferred sample of twins. J Am Acad Child Adolesc Psychiatry 38(11):1355–1362
Wong ML, Arcos-Burgos M, Licinio J (2008) Frontiers in psychiatric research. Psychiatr Times 25(7):1–8
Acknowledgments
The authors declare no competing financial interests. This research was supported by funds of the NHGRI intramural research program, NIH, Bethesda, MD, USA.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Arcos-Burgos, M., Muenke, M. Toward a better understanding of ADHD: LPHN3 gene variants and the susceptibility to develop ADHD. ADHD Atten Def Hyp Disord 2, 139–147 (2010). https://doi.org/10.1007/s12402-010-0030-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12402-010-0030-2