Bipolar disorder risk alleles in adult ADHD patients

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  • Genes, Brain and Behavior (2011) 10: 418423 doi: 10.1111/j.1601-183X.2011.00680.x

    Bipolar disorder risk alleles in adult ADHD patients

    E. T. Landaas,,, S. Johansson,,,A. Halmy,,, K. J. Oedegaard,,,O. B. Fasmer,, and J. Haavik,,,

    Department of Biomedicine, University of Bergen, K.G.Jebsen Centre for Research on Neuropsychiatric Disorders,University of Bergen Centre of Medical Genetics andMolecular Medicine, Haukeland University Hospital,**Department of Clinical Medicine, Section for Psychiatry,Faculty of Medicine, University of Bergen, and Division ofPsychiatry, Haukeland University Hospital, Bergen, Norway*Corresponding author: J. Haavik, Department of Biomedicine,University of Bergen, Bergen, Norway.E-mail:

    Attention-deficit/hyperactivity disorder (ADHD) has anestimated prevalence of 35% in adults. Genome-wideassociation (GWA) studies have not been performedin adults with ADHD and studies in children have sofar been inconclusive, possibly because of the smallsample sizes. Larger GWA studies have been performedon bipolar disorder (BD) and BD symptoms, and severalpotential risk genes have been reported. ADHD and BDshare many clinical features and comorbidity betweenthese two disorders is common. We therefore wantedto examine whether the reported BD genetic variantsin CACNA1C, ANK3, MYO5B, TSPAN8 and ZNF804Aloci are associated with ADHD or with scores on theMood Disorder Questionnaire (MDQ), a commonly usedscreening instrument for bipolar spectrum disorders. Westudied 561 adult Norwegian ADHD patients and 711controls from the general population. No significantassociations or trends were found between any ofthe single nucleotide polymorphisms (SNPs) studiedand ADHD [odds ratios (ORs) 1.05]. However, a weakassociation was found between rs1344706 in ZNF804A(OR = 1.25; P = 0.05) and MDQ. In conclusion, it seemsunlikely that these six SNPs with strong evidence ofassociation in BD GWA studies are shared risk variantsbetween ADHD and BD.

    Keywords: ADHD, ANK3, BD, CACNA1C, genetics, GWAstudies, MDQ, MYO5B, TSPAN8, ZNF804A

    Received 21 October 2010, revised 11 January 2011,accepted for publication 25 January 2011

    Attention-deficit/hyperactivity disorder (ADHD) is a neuropsy-chiatric disorder characterized by hyperactivity, impulsivityand inattention. Initially it was considered a childhood condi-tion, but it has become increasingly evident that symptoms

    frequently persist into adulthood (Faraone et al. 2006), andthe prevalence of ADHD has been estimated to be inthe range of 35% in adults (Fayyad et al. 2007; Kessleret al. 2006).

    Affective symptoms are common in adult ADHD patients,constitute an important feature of the disorder (Reimherret al. 2005), and it has been suggested that such symptomsshould be among the diagnostic criteria in adults (Wenderet al. 1981). Comorbidity with other psychiatric disorders isalso common in adult ADHD patients (Haavik et al. 2010;Mcgough et al. 2005; Sobanski et al. 2007), and one of thefrequently reported co-occurring diagnoses is bipolar disor-der (BD) (Wingo & Ghaemi 2007). In addition to affectivesymptoms, individuals with BD and ADHD show overlappingsymptoms such as impaired impulse control and dysreg-ulation of energy and activity levels (Skirrow et al. 2009).We have previously reported that approximately 12% of ouradult ADHD patients have self-reported comorbidity with BD(Halmoy et al. 2010). However, 51% of the patients screenedpositive on the Mood Disorder Questionnaire (MDQ), ascreening instrument for bipolar spectrum disorders (BSD)(Hirschfeld et al. 2000), showing that symptoms of maniaand hypomania are highly prevalent in adult ADHD patientsalso in the absence of a diagnosed BD. Neuroimaging studiesare also compatible with partially overlapping pathogeneticmechanisms in these conditions (Passarotti et al. 2010).

    The heritability of childhood ADHD has been estimatedto be about 76% (Faraone et al. 2005). Although many link-age and candidate association studies have been performedin the search for susceptibility genes, findings have beeninconsistent and contradictory (Franke et al. 2009). Overrecent years, genome-wide association (GWA) studies haveresulted in a large number of genetic variants showing highlysignificant associations with traits in several medical spe-cialities (McCarthy 2010; Teslovich et al. 2010), althoughoften with relatively modest effect sizes. However, concern-ing ADHD, no gene region has been established at wholegenome significance so far (Franke et al. 2009). Althoughprogress has been slow even for most other common com-plex mental disorders, there have been some promisingresults, especially in BD, where the numbers of samplesstudied have been considerably larger than for ADHD.

    As both BD and ADHD are highly heritable and often co-occur within families (Birmaher et al. 2010; Faraone et al.1997), one could hypothesize that the two disorders mightshare some common genetic risk factors (Hegerl et al. 2010).The aim of this study was to examine whether singlenucleotide polymorphism (SNP) alleles found associatedwith BD through recent GWA studies are more commonin patients with persistent ADHD than in controls recruitedfrom the general population. We chose to study six SNPs,of which five are located in or near the genes encodingankyrinG (ANK3) (Ferreira et al. 2008), myosin5B (MYO5B),

    418 2011 The AuthorsGenes, Brain and Behavior 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society

  • Bipolar disorder risk alleles in adult ADHD patients

    tetraspanin-8 (TSPAN8) and the alpha 1C subunit of anL-type voltage-dependent calcium channel (CACNA1C) (Sklaret al. 2008). The sixth SNP is located in the zinc fingerprotein 804A gene (ZNF804A), a gene that was first foundassociated with schizophrenia in a GWA study, but wasfurther found associated with BD, because the P-valuebecame genome-wide significant only after individuals withBD were included in the original patient sample (ODonovanet al. 2008). Additionally, we wanted to test if there was anyassociation between these SNPs and scores on the MDQ.

    Material and methods

    SubjectsOur sample consists of 1272 Caucasians of Norwegian ancestry, allof more than 18 years of age. Of these, 561 were patients diagnosedwith ADHD according to ICD-10 research criteria (World HealthOrganization 1993), with two modifications: allowing the inattentivesubtype in DSM-IV as sufficient for the diagnosis and allowing for thepresence of comorbid psychiatric disorders, as long as the criteria forADHD were present before the appearance of the comorbid disorder(Johansson et al. 2008). These diagnostic criteria are very similarto the DSM-IV criteria for ADHD (American Psychiatric Association2000). The majority of the patients were recruited by responding toan invitation sent by letter to their addresses, as listed in a Norwegiannational registry of adult ADHD patients. The remainder was recruiteddirectly from psychiatrists or out-patient clinics (Johansson et al.2008). Patients who reported mental retardation were excludedfrom analyses. The control group consisted of 711 volunteers fromthe general population (aged 1840 years) recruited from all acrossNorway for the purpose of this study (described in Halmoy et al.2010). Controls were unselected, i.e. no controls were excludedbased on the presence of life-time psychiatric disorders or otherrelated traits. A written informed consent was obtained from allparticipants and the study was approved by the Norwegian RegionalMedical Research Ethics Committee West IRB #3 (FWA00009490,IRB00001872).

    MeasuresAll participants returned a questionnaire, where current and life-timepsychiatric morbidity was reported (Halmy et al. 2010). Additionally,they filled in the MDQ, which is a screening instrument designed tofacilitate the recognition of BSD (Hirschfeld et al. 2000). A positivescore is defined as 7 (of 13) positive items concerning life-timesymptoms of mania and hypomania, co-occurrence of at least two ofthese symptoms and functional impairment caused by the symptomsrated as moderate to severe. MDQ has been validated for use in bothhealthy and psychiatrically ill individuals (Hirschfeld et al. 2000, 2003).For the quantitative MDQ analyses, all individuals with missing itemswere excluded, resulting in analyses of 503 ADHD patients (90%)and 681 controls (96%). A few individuals fulfilled the criteria forMDQ positive or negative despite having missing items, and thusthe dichotomous MDQ analyses included 517 ADHD patients (92%)and 691 controls (97%).

    SNP selection and genotypingSelection of SNPs was based on a literature search as of January2010. SNPs that had been emphasized as likely to be associatedwith BD, at a level of genome-wide significance (P < 5.0 108)or near such values, either in BD GWA studies alone [rs9804190(Schulze et al. 2009); rs10994336 (Ferreira et al. 2008); rs1006737,rs1705236 and rs4939921 (Sklar et al. 2008)] or in combination withschizophrenia cases [rs1344706 in ZNF804A (ODonovan et al. 2008)]were selected as candidates for genotyping in our sample. Only oneSNP, with the strongest P-value, was chosen for each locus tolimit multiple testing issues, except for the ANK3 locus where two

    SNPs were selected as studies have pointed to two independentsignals. The DGKH (diacylglycerol kinase eta) SNP rs1012053 (Baumet al. 2008) failed in assay design and was not included in theanalysis.

    Samples of either whole blood or saliva were obtained fromall participants, and the Oragene DNA Self-Collection Kit (DNAGenotek Inc., Ontario, Canada) was used for DNA extraction. TheDNA was aliquoted into 96-well plates, each of which contained DNAfrom both cases and controls and a minimum of two blank samplesand two internal controls. SNP genotyping was performed using theMassARRAY iPLEX System (Sequenom, San D


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