Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11

Abstract

Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL]-log[P value] = 5.49 at approximately 128 cM), and 17p11 (multipoint NPL-log [P value] >12 at approximately 12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at approximately 12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL-log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes.

Figure 1

Pedigree structure of 16 multigenerational Paisa families. ADHD affection status is shown in black. DNA samples that were subjected to genotyping are indicated by a dot. Pedigrees have been modified to protect confidentiality.

Figure 2

Results of a genomewide scan of 16 families with ADHD. Two-point LOD scores that are >2.0 per chromosome (as estimated by FASTLINK), for a recombination value of θ=0, are shown as blackened circles; −log (P value) of the two-point NPL E-STAT >2.0 per chromosome for each marker (as estimated by SIMWALK2) are depicted as blackened triangles, and −log (P value) of the PDT Z statistic values >2.0 per chromosome at each marker for the whole set of families together are shown as blackened squares. Two different symbols at the same marker indicate either two positive families or, in the case of NPL statistics, a combined positive result for the whole set of families. Multipoint location scores, for those families exhibiting scores >2.0 (as estimated by SIMWALK2) in any region of the chromosome, are presented as colored lines. Black lines represent the parametric multipoint location scores per chromosome in the combined families. Linkage analysis of the X chromosome does not report any value >2.0

Figure 3

Linkage results of the fine mapping of five regions (4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11) in 16 families with ADHD. Two-point LOD scores >2.0 per chromosome (as estimated by FASTLINK), for a recombination value of θ=0, are shown as blackened circles; −log (P value) of the two-point NPL E-STAT >2.0 per chromosome for each marker (as estimated by SIMWALK2) are shown as blue circles and triangles (significant combined results), and −log (P value) of the PDT Z statistic values >2.0 per chromosome at each marker for the whole set of families are indicated as green (conferring susceptibility) and red (conferring protection) squares. Two different symbols at the same marker indicate either two positive families or, in the case of NPL statistics, a combined positive result for the whole set of families. Two squares at the same marker indicate either that two alleles are in LD or that there was concordance between the two kinds of PDT (i.e., sum and average). Multipoint location scores, as estimated by SIMWALK2, for those families exhibiting scores >2.0 in any region of the chromosome, are presented as colored lines. Black lines represent the parametric multipoint location scores per chromosome in the combined families.

Figure 4

Model-free linkage results of the fine mapping of five regions (4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11) in 16 families with ADHD. Two-point LOD scores >2.0, estimated by the conditional logistic model (Olson 1999) by use of LODPAL in SAGE, version 4.5, are shown as blackened circles. Continuous lines represent the −log (P value) of the multipoint NPL E-STAT per chromosome, as estimated by MERLIN (colored lines represent specific families, and black lines denote the combined set of all families).

Figure 5

Family structure haplotypes of three informative pedigrees that show those chromosomal regions segregating with ADHD at chromosomes 4q13.2, 11q22, and 17p11. Haplotypes were reconstructed using SIMWALK2, and they are shown for family F8 at 11q22, family F9 at 4q13.2, and family F14 at 17p11, with markers listed close to the top left symbol.

Figure 5

Family structure haplotypes of three informative pedigrees that show those chromosomal regions segregating with ADHD at chromosomes 4q13.2, 11q22, and 17p11. Haplotypes were reconstructed using SIMWALK2, and they are shown for family F8 at 11q22, family F9 at 4q13.2, and family F14 at 17p11, with markers listed close to the top left symbol.

Figure 5

Family structure haplotypes of three informative pedigrees that show those chromosomal regions segregating with ADHD at chromosomes 4q13.2, 11q22, and 17p11. Haplotypes were reconstructed using SIMWALK2, and they are shown for family F8 at 11q22, family F9 at 4q13.2, and family F14 at 17p11, with markers listed close to the top left symbol.