Genome-wide linkage analysis of ADHD using high- density SNP ...

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5q13.1 was detected in an analysis across all families and also scored high in two individual families suggesting that the identified region contains a common gene variant. Approximately 350 kb upstream of the linkage peak the PIK3R1 gene is located, coding for a regulatory subunit of the phosphatidylinositol 3-kinase protein involved in post-receptor signaling. PIK3R1 is strongly expressed in the prefrontal cortex, a brain region implicated in ADHD symptoms and stimulant treatment response. 42 Although genes within replicated linkage regions seem especially promising for fine mapping and Genome-wide linkage analysis of ADHD M Romanos et al Figure 2 Genome-wide parametric linkage results in eight families under the narrow phenotype assumption (red, MODglobal; blue, MODsingle). Figure 3 Genome-wide parametric linkage results in eight families under the broad phenotype assumption (red, MODglobal; blue, MODsingle). subsequent positional cloning efforts, candidate genes may also be found in novel loci, such as the syntaxin-binding protein 6 gene (STXBP6) located within the MCR of the locus at 14q12. STXBP6 is involved in neurotransmitter release, and interacts with synaptosome-associated protein receptors including SNAP 25. 10 The genes encoding the g-aminobutyric-acid (GABA) receptor subunit b-3 (GABRB3) and the amyloid b-A4 precursor proteinbinding member 2 (APBA2) are located in the center of the MCR at 15q12-13.1 (P2). GABRB3 is encoding a subunit of the GABA/benzodiazepine receptor 527 Molecular Psychiatry
528 Molecular Psychiatry Table 3 Linkage results in individual families Locus Info Narrow Broad MCR DI fam n/r MODglobal MODsingle NPL MODglobal MODsingle NPL Marker Physical position (in Mb) Genome-wide linkage analysis of ADHD M Romanos et al 1q25.1 0.95 4.17 4.17 7.34 1.79 1.79 4.33 rs1234315 169.91 1.00 P2 r 1q25.3 0.92 2.99 2.99 6.00 0.85 0.91 0.68 rs2274984-rs2148620 179.84–180.43 0.98 P8 r 9q31.1-33.1 0.88 1.50 1.50 3.20 2.59 2.59 9.51 rs1809921-rs7861999 104.89–112.20 1.00 P1 r 9q33 0.73 2.52 2.52 5.67 1.91 1.91 3.41 rs230150-rs10513454 119.03–125.75 0.98 P5 r 12p13.33 0.96 3.11 3.11 5.12 2.32 2.32 5.28 rs4980804-rs1009281 0.13–2.40 0.08 P2 r 15q11.2-13.3 0.95 3.68 3.68 4.68 1.97 1.97 1.84 rs4310812-rs3850097 19.85–31.20 0.68 P2 r 16p12.3-12.2 0.89 1.41 2.11 1.69 3.84 3.84 4.47 rs10492784-rs226042 19.27–21.20 1.00 P1 r 18q11.2-12.3 0.95 2.90 2.90 5.31 1.82 1.82 4.09 rs1623173-rs2543029 20.08–41.35 0.34 P2 n For further annotations, please see Table 2. complex mediating the effects of the major inhibitory neurotransmitter, and the APBA2 product is involved in synaptic vesicle docking/fusion by interacting with STXBP1. 43 Linkage findings across all eight families resulted from the contributions of 3–7 families (family score > 0). Particular for the linkage region at 5q13.1 (MODglobal 4.16, all families, broad phenotype), families P1 and P3 also showed relatively high scores (MODglobal > 2.7, broad phenotype) under a similar genetic model. The other linkage study that investigated extended pedigrees segregating for ADHD 14 only detected a single linkage region at 4q13.2 that corresponded in two distinct families. Even though a large set of families originating from the same genetic isolate (n = 16) was investigated, no further linkage peaks across families were found. In our study, all loci identified in individual families were replications of previous linkage scans in ADHD with the exception of the locus at 18p11.2-12.3. Therefore, candidate genes at these loci not only may be specific risk factors for ADHD in the respective family, but are also likely to represent common predisposing factors. The novel locus on chromosome 18, however, requires replication. Notably, our study replicated results from genome-wide scans in affected sib-pairs further emphasizing the epidemiological relevance of our findings. Overlap with loci identified in the genetic isolate was only found for regions obtained by analysis of comorbid ODD or CD. 14 Since comorbid behavioral problems are frequent in ADHD, comorbidity with CD has been suspected to indicate a genetically more pronounced variant of ADHD. 35,44 Pleiotropy and variable genetic dispositions between different population groups may account for the discrepant results of the two extended pedigree-based scans. 14,35 With the application of a genome-wide highdensity scan, our results appear to provide a more accurate estimation of localization of candidate gene loci than the classical micro-satellite approach. Therefore, variance in the location of linkage peaks might, in part, be due to these alternative approaches. Differences between studies may also result from low statistical power to detect true linkage due to small sample size. 36 Although the total number of the investigated individuals is comparatively small in our study, the specific family structure and the dense segregation of ADHD substantially increased statistical power, and might have facilitated replication of previously reported linkage. The pattern of bilineality observed in some of our families possibly decreased power to detect true linkage, but on the other hand reflected an inherent tendency toward assortative mating commonly observed for ADHD. Thus, including bilineal families might support the notion that observed linkage—especially when replicated— will be of relevance for the prevalence of ADHD in the general population. The loss of power due to genetic heterogeneity caused by bilineality can be partially counteracted by taking all results of appropriate
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