Suggestive linkage of ADHD to chromosome 18q22 in a young genetically isolated Dutch population

Genetic Epidemiology Unit, Department of Epidemiology & Biostatistics and Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
European journal of human genetics: EJHG (Impact Factor: 4.35). 01/2009; 17(7):958-66. DOI: 10.1038/ejhg.2008.260
Source: PubMed


Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable, neuropsychiatric disorder among children. Linkage studies in isolated populations have proved powerful to detect variants for complex diseases, such as ADHD. We performed a genome-wide linkage scan for ADHD in nine patients from a genetically isolated population in the Netherlands, who were linked to each other within 10 generations through multiple lines of descent. The genome-wide scan was performed with a set of 400 microsatellite markers with an average spacing of +/-10-12 cM. We performed multipoint parametric linkage analyses using both recessive and dominant models. Our genome scan pointed to several chromosomal regions that may harbour ADHD susceptibility genes. None exceeded the empirical genome-wide significance threshold, but the Log of odds (LOD) scores were >1.5 for regions 6p22 (Heterogenetic log of odds (HLOD)=1.67) and 18q21-22 (HLOD=2.13) under a recessive model. We followed up these two regions in a larger sample of ADHD patients (n=21, 9 initial and 12 extra patients). The LOD scores did not increase after increasing the sample size (6p22 (HLOD=1.51), 18q21-22 (HLOD=1.83)). However, the LOD score on 6p22 increased to 2 when a separate analysis was performed for the inattentive type ADHD children. The linkage region on chromosome 18q overlaps with the findings of association of rs2311120 (P=10(-5)) and rs4149601 (P=10(-4)) in the genome-wide association analysis for ADHD performed by the Genetic Association Information Network consortium. Furthermore, there was an excess of regions harbouring serotonin receptors (HTR1B, HTR1E, HTR4, HTR1D, and HTR6) that showed a LOD score >1 in our genome-wide scan.

Download full-text


Available from: Robert F Ferdinand, Jan 14, 2014
  • Source
    • "Our significant QTL for inattention on chromosome 18q21.1– 18q22.3 has previously shown a suggestive linkage in the young genetically isolated population from the Netherlands using the Dutch version of the NIMH Diagnostic Interview Schedule for children that utilizes ADHD DSM-IV diagnostic criteria for the phenotypic definition [Amin et al., 2009]. An intergenic rs2311120 SNP on 18q21.2 was recently reported to be the third most associated SNP after the TDT-bias correction (P ¼ 1.22EÀ05) [Neale et al., 2008]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental phenotype that persists into adulthood. This study investigated the heritability of inattentive and hyperactive symptoms and of total ADHD symptomatology load (ADHD index) in adults and performed linkage scans for these dimensions. Data on sibling pairs and their family members from the Netherlands Twin Register with genotype and phenotype data for inattention, hyperactivity and ADHD index (∼750 sib-pairs) were analyzed. Phenotypes were assessed with the short self-report form of the Conners' Adult ADHD Rating Scales (CAARS). Heritabilities were estimated in SOLAR under polygenic models. Genome-wide linkage scans were performed using variance components (VC) in MERLIN and MINX and model-based linkage analysis was carried out in MENDEL with empirical evaluation of the results via simulations. Heritability estimates for inattention, hyperactivity and ADHD index were 35%, 23%, and 31%, respectively. Chromosomes 18q21.31-18q21.32 (VC LOD = 4.58, p(emp)  = 0.0026) and 2p25.1 (LOD = 3.58, p(emp)  = 0.0372) provided significant evidence for linkage for inattention and the ADHD index, respectively. The QTL on chromosome 2p25.1 also showed suggestive linkage for hyperactivity. Two additional suggestive QTLs for hyperactivity and the ADHD index shared the same location on chromosome 3p24.3-3p24.1. Finally, a suggestive QTL on 8p23.3-8p23.2 for hyperactivity was also found. Heritability of inattention, hyperactivity and total ADHD symptoms is lower in adults than in children. Chromosomes 18q and 2p are likely to harbor genes that influence several aspects of adult ADHD.
    Full-text · Article · Apr 2011 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder. Genetics has an important role in the aetiology of this disease. In this study, we describe the clinical findings in a Dutch family with eight patients suffering from ADHD, in whom five had at least one other psychiatric disorder. We performed a genome-wide (parametric and nonparametric) affected-only linkage analysis. Two genomic regions on chromosomes 7 and 14 showed an excess of allele sharing among the definitely affected members of the family with suggestive LOD scores (2.1 and 2.08). Nonparametric linkage analyses (NPL) yielded a maxNPL of 2.92 (P=0.001) for marker D7S502 and a maxNPL score of 2.56 (P=0.003) for marker D14S275. We confirmed that all patients share the same haplotype in each region of 7p15.1-q31.33 and 14q11.2-q22.3. Interestingly, both loci have been reported before in Dutch (affected sib pairs) and German (extended families) ADHD linkage studies. Hopefully, the genome-wide association studies in ADHD will help to highlight specific polymorphisms and genes within the broad areas detected by our, as well as other, linkage studies.
    Full-text · Article · Sep 2009 · European journal of human genetics: EJHG
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormalities in electrophysiological measures of stimulus-evoked brain activity (including the P3 event-related potential (ERP) and its associated delta and theta time-frequency (TF) components), and intrinsic, resting state brain activity (including EEG in the beta frequency band) have each been associated with biological vulnerability to a variety of externalizing (EXT) spectrum disorders, such as substance use disorders, conduct disorder, and antisocial behavior. While each of these individual measures has shown promise as an endophenotype for one or more aspects of EXT, we proposed that the power to identify EXT-related genes may be enhanced by using these measures collectively. Thus, we sought to explore a multivariate approach to identifying electrophysiological endophenotypes related to EXT, using measures identified in the literature as promising individual endophenotypes for EXT. Using data from our large twin sample (634 MZ and 335 DZ, male and female same-sex pairs), and fitting multivariate biometric Cholesky models, we found that these measures (1) were heritable, (2) showed significant phenotypic and genetic correlation with a general vulnerability to EXT (which is itself highly heritable), (3) showed modest phenotypic and genetic correlation with each other, and (4) were sensitive to genetic effects that differed as a function of gender. These relationships suggest that these endophenotypes are likely tapping into neurophysiological processes and genes that are both common across them and unique to each-all of which are relevant to a biological vulnerability to EXT psychopathology.
    Full-text · Article · Feb 2010 · Behavior Genetics
Show more