| Summary |
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 selfreport 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, emp P-value=0.0026) and 2p25.1 (LOD=3.58, emp P-value=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. |
| Total Sample |
Several microsatellite genotyping steps were undertaken for the NTR families. These steps resulted in a sample of 711 families with 3,412 non-clone individuals (1,438 founders, 1,870 females) with an average of 4.8 subjects per family, with 99.2% of families comprising two generations and 0.8% comprising three generations. Both founders were genotyped in 282 of these families and another 138 families had one genotyped founder. In addition, there were 290 nuclear families with no genotyped founders, and one extended pedigree with four founders without genotypes. For more information about the description of the NTR linkage pedigree sample utilized for Variance Components (VC) and parametric analyses, please refer to the original publication. A group of 192 unrelated subjects completed the CAARS a second time after 6 months to obtain retest data. |
| Sample Collection |
The NTR focuses on longitudinal phenotypic and biological data collection in Dutch twins and their family members [Boomsma et al., 2006]. The current study analyses phenotype data from the 7th survey [Distel et al., 2007]. The study was approved by the Central Ethics Committee on Research involving human subjects of the VU University Medical Centre, Amsterdam, an Institutional Review Board certified by the US Office of Human Research Protections (IRB number IRB-2991 under Federal-wide Assurance-3703; IRB/institute codes, NTR 03-180). |
| Diagnosis Description |
The 30-item screening self-report form of the CAARS [Conners et al., 1999] was included into the 7th NTR survey and provided a quantitative assessment of the inattentive symptoms (inattention) using a 9-item subscale, hyperactive-impulsive symptoms (hyperactivity) using a 9-item subscale, and the total ADHD symptom 12-item subscale, known as ADHD index. There were no overlapping items among the three subscales. The items on the inattention and hyperactivity scales correspond to the symptoms that represent the diagnostic criteria of adult ADHD as outlined in DSM-IV-TR. The ADHD index is a tool for the screening of cumulative ADHD symptoms and is designed to discriminate between adults affected with ADHD and a non clinical group. Every item was scored on a scale from 1 to 4 and a sum score was obtained for each of the phenotypic subscales. Missing items were handled as per CAARS instructions [Conners et al., 1999] which allows the scoring of scales with up to two miss ng items. Data for 34 participants were discarded due to monotonous responses on every item for every scale. |
| Technique |
Genotype quality control was undertaken separately within each batch. The physical position of microsatellites was obtained from the direct query in silico PCR on the March 2006 NCBI36/hg18 build of Human Genome [Kent et al., 2002]. Using the physical position and the Rutgers Map Interpolator that utilizes the second-generation combined linkage-physical maps, the genetic position of each marker was obtained [Matise et al., 2007]. For more details, please refer to the original publication. |
| Analysis Method |
Genome-Wide Linkage Analysis: The genetic maps obtained through the Rutgers University Map Interpolator were adjusted so that the most distal marker on the p-arm of each chromosome started at the genetic position of 0.0cM. These maps were used for both VC and parametric linkage scans. The allele frequencies were estimated with the MENDEL v.10.0 using model 1 of option 6. Both genome scans were performed at 1cM resolution. Both software packages can handle the presence of monozygotic (MZ) twins in the linkage sample. The VC linkage scan of the autosomal genome was conducted with MERLIN v.1.1.2 using the multipoint identity-by-descent (IBD) information with age and sex as covariates. The MINX version of MERLIN was used for the VC linkage analysis of chromosome X. For the parametric analysis, they first estimated genotypic model parameters for each phenotype using option 14 of MENDEL. Further, MENDEL's model 2 of option 14 was used to define the individual genotype penetrance for each phenotyped subject. Parametric linkage analysis was performed with the Location Score option 2. Empirical significance evaluation was simulated to assess the significance of the autosomal portion of the linkage scan results. The reported 95% confidence in tervals for the empirical P values are obtained with BINOM [Ott, 1991]. The LOD scores observed at the empirical significance levels of 0.01, 0.05, 0.1, and 0.50 for each phenotype in VC and parametric linkage scans were listed in original publication as revealed by simulations. The LOD values corresponding to the empirical levels of 0.50 and 0.05 were used to declare the 'suggestive' and 'significant' areas of linkage. For more details, please refer to the orginal publication. |
| Result Description |
Chromosomes 18q21.31-18q21.32 (VC LOD=4.58, emp P-value=0.0026) and 2p25.1 (LOD=3.58, emp P-value=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. |
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