Top

Published in:

01-08-2016 | Psychiatry and Preclinical Psychiatric Studies - Original Article

The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits

Authors: Christine M. Freitag, Thomas Lempp, T. Trang Nguyen, Christian P. Jacob, Lena Weissflog, Marcel Romanos, Tobias J. Renner, Susanne Walitza, Andreas Warnke, Dan Rujescu, Klaus-Peter Lesch, Andreas Reif

Published in: Journal of Neural Transmission | Issue 8/2016

Abstract

Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N = 592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p = 0.025). This was not observed in the adult case–control sample alone, but retained in the combined sample (nominal p = 0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits.

Available only for authorised users

Achenbach TM, Dumenci L, Rescorla LA (2003) DSM-oriented and empirically based approaches to constructing scales from the same item pools. J Clin Child Adolesc Psychol 32:328–340CrossRefPubMed

Adkins DE, Aberg K, McClay JL, Bukszar J, Zhao Z, Jia P, Stroup TS, Perkins D, McEvoy JP, Lieberman JA, Sullivan PF, Van den Oord EJ (2011) Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Mol Psychiatry 16:321–332CrossRefPubMed

American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders (DSM-5), 5th edn. American Psychiatric Association, Washington, DC, London

Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls DL, Monsuur AJ, van’t Slot R, Minderaa RB, Gunning WB, Pearson PL, Sinke RJ (2003) A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet 72:1251–1260CrossRefPubMedPubMedCentral

Becker T, Knapp M (2004) Maximum-likelihood estimation of haplotype frequencies in nuclear families. Genet Epidemiol 27:21–32CrossRefPubMed

Brikell I, Kuja-Halkola R, Larsson H (2015) Heritability of attention-deficit hyperactivity disorder in adults. Am J Med Genet B Neuropsychiatr Genet

Chen WM, Deng HW (2001) A general and accurate approach for computing the statistical power of the transmission disequilibrium test for complex disease genes. Genet Epidemiol 21:53–67CrossRefPubMed

Cloninger CR, Przybeck TR, Svrakic DM (1991) The tridimensional personality questionnaire: US normative data. Psychol Rep 69:1047–1057CrossRefPubMed

Costa PT Jr, McCrae RR (1995) Domains and facets: hierarchical personality assessment using the revised NEO personality inventory. J Pers Assess 64:21–50CrossRefPubMed

Downey KK, Stelson FW, Pomerleau OF, Giordani B (1997) Adult attention deficit hyperactivity disorder: psychological test profiles in a clinical population. J Nerv Ment Dis 185:32–38CrossRefPubMed

Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL, Newbury DF, Crawford LR, Palmer CG, Woodward JA, Del’Homme M, Cantwell DP, Nelson SF, Monaco AP, Smalley SL (2002) A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet 70:1183–1196CrossRefPubMedPubMedCentral

Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J, Boreatti-Hummer A, Heine M, Jacob CP, Lesch KP, Casas M, Ribases M, Bosch R, Sanchez-Mora C, Gomez-Barros N, Fernandez-Castillo N, Bayes M, Halmoy A, Halleland H, Landaas ET, Fasmer OB, Knappskog PM, Heister AJ, Kiemeney LA, Kooij JJ, Boonstra AM, Kan CC, Asherson P, Faraone SV, Buitelaar JK, Haavik J, Cormand B, Ramos-Quiroga JA, Reif A (2010) Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology 35:656–664CrossRefPubMed

Franke B, Faraone SV, Asherson P, Buitelaar J, Bau CH, Ramos-Quiroga JA, Mick E, Grevet EH, Johansson S, Haavik J, Lesch KP, Cormand B, Reif A (2012) The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 17:960–987CrossRefPubMed

Freitag CM, Rohde LA, Lempp T, Romanos M (2010) Phenotypic and measurement influences on heritability estimates in childhood ADHD. Eur Child Adolesc Psychiatry 19:311–323CrossRefPubMed

Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155:478–484CrossRefPubMed

Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569–573CrossRefPubMedPubMedCentral

Hawi Z, Cummins TD, Tong J, Johnson B, Lau R, Samarrai W, Bellgrove MA (2015) The molecular genetic architecture of attention deficit hyperactivity disorder. Mol Psychiatry 20:289–297CrossRefPubMed

Hebebrand J, Dempfle A, Saar K, Thiele H, Herpertz-Dahlmann B, Linder M, Kiefl H, Remschmidt H, Hemminger U, Warnke A, Knolker U, Heiser P, Friedel S, Hinney A, Schafer H, Nurnberg P, Konrad K (2006) A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs. Mol Psychiatry 11:196–205CrossRefPubMed

Jacob CP, Romanos J, Dempfle A, Heine M, Windemuth-Kieselbach C, Kruse A, Reif A, Walitza S, Romanos M, Strobel A, Brocke B, Schafer H, Schmidtke A, Boning J, Lesch KP (2007) Comorbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 257:309–317CrossRefPubMed

Jain M, Palacio LG, Castellanos FX, Palacio JD, Pineda D, Restrepo MI, Munoz JF, Lopera F, Wallis D, Berg K, Bailey-Wilson JE, Arcos-Burgos M, Muenke M (2007) Attention-deficit/hyperactivity disorder and comorbid disruptive behavior disorders: evidence of pleiotropy and new susceptibility loci. Biol Psychiatry 61:1329–1339CrossRefPubMed

Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997) Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–988CrossRefPubMed

Lahey BB, Van Hulle CA, Singh AL, Waldman ID, Rathouz PJ (2011) Higher-order genetic and environmental structure of prevalent forms of child and adolescent psychopathology. Arch Gen Psychiatry 68:181–189CrossRefPubMedPubMedCentral

Laird NM, Horvath S, Xu X (2000) Implementing a unified approach to family-based tests of association. Genet Epidemiol 19(Suppl 1):S36–S42CrossRefPubMed

Lara C, Fayyad J, De Graaf R, Kessler RC, Aguilar-Gaxiola S, Angermeyer M, Demytteneare K, de Girolamo G, Haro JM, Jin R, Karam EG, Lepine JP, Mora ME, Ormel J, Posada-Villa J, Sampson N (2009) Childhood predictors of adult attention-deficit/hyperactivity disorder: results from the World Health Organization World Mental Health Survey Initiative. Biol Psychiatry 65:46–54CrossRefPubMed

Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Roser C, Nguyen TT, Craig DW, Romanos J, Heine M, Meyer J, Freitag C, Warnke A, Romanos M, Schafer H, Walitza S, Reif A, Stephan DA, Jacob C (2008) Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm 115:1573–1585CrossRefPubMed

Lionel AC, Tammimies K, Vaags AK, Rosenfeld JA, Ahn JW, Merico D, Noor A, Runke CK, Pillalamarri VK, Carter MT, Gazzellone MJ, Thiruvahindrapuram B, Fagerberg C, Laulund LW, Pellecchia G, Lamoureux S, Deshpande C, Clayton-Smith J, White AC, Leather S, Trounce J, Melanie BH, Hatchwell E, Eis PS, Yuen RK, Walker S, Uddin M, Geraghty MT, Nikkel SM, Tomiak EM, Fernandez BA, Soreni N, Crosbie J, Arnold PD, Schachar RJ, Roberts W, Paterson AD, So J, Szatmari P, Chrysler C, Woodbury-Smith M, Brian LR, Zwaigenbaum L, Mandyam D, Wei J, Macdonald JR, Howe JL, Nalpathamkalam T, Wang Z, Tolson D, Cobb DS, Wilks TM, Sorensen MJ, Bader PI, An Y, Wu BL, Musumeci SA, Romano C, Postorivo D, Nardone AM, Monica MD, Scarano G, Zoccante L, Novara F, Zuffardi O, Ciccone R, Antona V, Carella M, Zelante L, Cavalli P, Poggiani C, Cavallari U, Argiropoulos B, Chernos J, Brasch-Andersen C, Speevak M, Fichera M, Ogilvie CM, Shen Y, Hodge JC, Talkowski ME, Stavropoulos DJ, Marshall CR, Scherer SW (2014) Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. Hum Mol Genet 23:2752–2768CrossRefPubMed

Lobbestael J, Leurgans M, Arntz A (2011) Inter-rater reliability of the structured clinical interview for DSM-IV Axis I disorders (SCID I) and Axis II disorders (SCID II). Clin Psychol Psychother 18:75–79CrossRefPubMed

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 67:146–154CrossRefPubMedPubMedCentral

Neuman RJ, Heath A, Reich W, Bucholz KK, Madden PAF, Sun L, Todd RD, Hudziak JJ (2001) Latent class analysis of ADHD and comorbid symptoms in a population sample of adolescent female twins. J Child Psychol Psychiatry 42:933–942CrossRefPubMed

O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266CrossRefPubMedPubMedCentral

Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164:942–948CrossRefPubMed

Rabinowitz D, Laird N (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 50:211–223CrossRefPubMed

Ranseen JD, Campbell DA, Baer RA (1998) NEO PI-R profiles of adults with attention deficit disorder. Assessment 5:19–24CrossRefPubMed

Renner TJ, Walitza S, Dempfle A, Eckert L, Romanos M, Gerlach M, Schafer H, Warnke A, Lesch KP, Jacob C (2008) Allelic variants of SNAP25 in a family-based sample of ADHD. J Neural Transm 115:317–321CrossRefPubMed

Romanos M, Freitag C, Jacob C, Craig DW, Dempfle A, Nguyen TT, Halperin R, Walitza S, Renner TJ, Seitz C, Romanos J, Palmason H, Reif A, Heine M, Windemuth-Kieselbach C, Vogler C, Sigmund J, Warnke A, Schafer H, Meyer J, Stephan DA, Lesch KP (2008) Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Mol Psychiatry 13:522–530CrossRefPubMed

Rosler M, Retz W, Retz-Junginger P, Stieglitz RD, Kessler H, Reimherr F, Wender PH (2008) Attention deficit hyperactivity disorder in adults. Benchmarking diagnosis using the Wender-Reimherr adult rating scale. Nervenarzt 79:320–327CrossRefPubMed

Rubia K, Alegria AA, Brinson H (2014) Brain abnormalities in attention-deficit hyperactivity disorder: a review. Rev Neurol 58(Suppl 1):S3–16PubMed

Schuler J, Weiss NT, Chavira DA, McGough JJ, Berrocal M, Sheppard B, Vaglio E, Fournier E, Herrera LD, Mathews CA (2012) Characteristics and comorbidity of ADHD sib pairs in the Central Valley of Costa Rica. Compr Psychiatry 53:379–386CrossRefPubMed

Sharp SI, McQuillin A, Marks M, Hunt SP, Stanford SC, Lydall GJ, Morgan MY, Asherson P, Curtis D, Gurling HM (2014) Genetic association of the tachykinin receptor 1 TACR1 gene in bipolar disorder, attention deficit hyperactivity disorder, and the alcohol dependence syndrome. Am J Med Genet B Neuropsychiatr Genet 165B:373–380CrossRefPubMed

Sheehan TJ (1996) Creating a psychosocial measurement model from stressful life events. Soc Sci Med 43:265–271CrossRefPubMed

Simon V, Czobor P, Balint S, Meszaros A, Bitter I (2009) Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry 194:204–211CrossRefPubMed

Uhl GR, Drgon T, Johnson C, Li CY, Contoreggi C, Hess J, Naiman D, Liu QR (2008) Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify “connectivity constellation” and drug target genes with pleiotropic effects. Ann N Y Acad Sci 1141:318–381CrossRefPubMedPubMedCentral

Vrijenhoek T, Buizer-Voskamp JE, van der Stelt I, Strengman E, Genetic Risk and Outcome in Psychosis (GROUP) Consortium, Sabatti C, Geurts van Kessel A, Brunner HG, Ophoff RA, Veltman JA (2008) Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am J Hum Genet 83:504–510CrossRefPubMedPubMedCentral

Waltes R, Duketis E, Knapp M, Anney RJ, Huguet G, Schlitt S, Jarczok TA, Sachse M, Kampfer LM, Kleinbock T, Poustka F, Bolte S, Schmotzer G, Voran A, Huy E, Meyer J, Bourgeron T, Klauck SM, Freitag CM, Chiocchetti AG (2014) Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders. Hum Genet 133:781–792CrossRefPubMed

Wang KS, Liu XF, Aragam N (2010) A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder. Schizophr Res 124:192–199CrossRefPubMed

Weber H, Scholz CJ, Jacob CP, Heupel J, Kittel-Schneider S, Erhardt A, Hempel S, Schmidt B, Kiel T, Gessner A, Lesch KP, Reif A (2014) SPOCK3, a risk gene for adult ADHD and personality disorders. Eur Arch Psychiatry Clin Neurosci 264:409–421CrossRefPubMed

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 38:1355–1362CrossRefPubMed

Wilson PM, Fryer RH, Fang Y, Hatten ME (2010) Astn2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. J Neurosci 30:8529–8540CrossRefPubMedPubMedCentral

Zheng C, Heintz N, Hatten ME (1996) CNS gene encoding astrotactin, which supports neuronal migration along glial fibers. Science 272:417–419CrossRefPubMed

Title: The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits
Authors: Christine M. Freitag
Thomas Lempp
T. Trang Nguyen
Christian P. Jacob
Lena Weissflog
Marcel Romanos
Tobias J. Renner
Susanne Walitza
Andreas Warnke
Dan Rujescu
Klaus-Peter Lesch
Andreas Reif
Publication date: 01-08-2016
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 8/2016
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-016-1553-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2016

Only complementary voices tell the truth: a reevaluation of validity in multi-informant approaches of child and adolescent clinical assessments

The aetiological association between the dynamics of cortisol productivity and ADHD

A candidate gene investigation of methylphenidate response in adult attention-deficit/hyperactivity disorder patients: results from a naturalistic study

Temporal integration of multisensory stimuli in autism spectrum disorder: a predictive coding perspective

Maturation of interhemispheric signal propagation in autism spectrum disorder and typically developing controls: a TMS-EEG study

Dimensional psychiatry: mental disorders as dysfunctions of basic learning mechanisms