DESCRIPTION:
A Summary of the SNPs That were Significant Within a Phenotype Using the PBAT Screening Algorithm with Various Quantitative Phenotypes. Families were collected by the International Multicenter ADHD Genetics (IMAGE) project. Families were identified through ADHD probands aged 5–17 attending outpatient clinics at the data collection sites in Europe and Israel. Patients had to meet clinical criteria for ADHD-combined type before being enrolled in the study. A total of 958 affected proband-parent trios were initially selected for the GWAS scan. Of these, 936 probands were initially ascertained as having DSM-IV combined type ADHD. Twenty-two probands who did not meet combined subtype ADHD diagnosis were included because they either met the criteria for the inattentive or hyperactive subtypes, or they missed the DSM-IV combined type diagnosis by a single item. Exclusion criteria were autism, epilepsy, IQ<70, brain disorders and any genetic or medical disorder associated with externalizing behaviors that might mimic ADHD. Six quantitative traits were generated for use in the association analyses, three from the Long Version of Conners' Parent Rating Scale (CPRS-R:L) and three from the Parental account of childhood symptom (PACS). Both the CPRS-R:L and the PACS assess the DSM-IV symptoms of ADHD in children and adolescents. The inattentive and hyperactive-impulsive symptoms included are: (1) inability to pay attention to details; (2) difficulty with sustained attention in tasks or play activities; (3) listening problems; (4) difficulty following instructions; (5) problems organizing tasks and activities; (6) avoidance or dislike of tasks that require mental effort; (7) tendency to lose things like toys, notebooks, or homework; (8) distractibility; (9) forgetfulness in daily activities; (10) fidgeting or squirming; (11) difficulty remaining seated; (12) restlessness; (13) difficulty playing quietly; (14) always seeming to be “on the go;” (15) excessive talking; (16) blurting out answers before hearing the full question; (17) difficulty waiting for a turn or in line; (18) problems with interrupting or intruding. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. Genotyping was performed by Perlegen Sciences using the Perlegen platform. Family-based association testing (FBAT) is a generalization of the Transmission Disequilibrium Test (TDT), which allows valid testing of association with any phenotype, sampling structure, and pattern of missing marker allele information [Horvath et al., 2001, 2004; Lange et al., 2004a]. We performed a cluster analysis in PLINK [Purcell et al., 2007] through a linkage clustering algorithm that is based on pairwise identity-by-state distance, to identify a predominant homogeneous cluster in our sample. Information from this cluster was used to rank-order the SNPs using the PBAT screening algorithm. It is important to note that the subset of individuals was used in the PBAT screening algorithm only. By using information from families that are not informative for a given SNP (a.k.a. the between information), PBAT selects a set of SNPs with the most power to detect association in a manner that does not bias the statistical test of association in the informative families [Lange et al., 2003a,b]. This reduces the number of independent comparisons by restricting the analysis to an abridged set of SNPs. Using PLINK a homogeneous cluster of 1,409 founders, including 660 families with both parents was identified. We used these 660 families in the PBAT screening algorithm from which the P-values of the top 10 ranked SNPs for each phenotype and genetic model (i.e. additive, dominant, recessive) combination were identified and the FBAT statistic was evaluated in the full sample. Two SNPs achieved significance within the specified GWAS analysis. From Table 2.
LABEL:
Sig. SNP FBAT–PC with inattentive ADHD symptoms dominant model_pvalue
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P-Value
THRESHOLD:
<= 0.5
GENES IN THRESHOLD:
1
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Genes in threshold: 1
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