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Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12

Abstract

Previous genome-wide linkage studies applied the affected sib-pair design; one investigated extended pedigrees of a genetic isolate. Here, results of a genome-wide high-density linkage scan of attention-deficit/hyperactivity disorder (ADHD) using an array-based genotyping of 50 K single nucleotide polymorphism (SNPs) markers are presented. We investigated eight extended pedigrees of German origin that were non-related, not part of a genetic isolate and ascertained on the basis of clinical referral. Two parametric analyses maximizing LOD scores (MOD) and a non-parametric analysis for both a broad and a narrow phenotype approach were conducted. Novel linkage loci across all families were detected at 2q35, 5q13.1, 6q22-23 and 14q12, within individual families at 18q11.2-12.3. Further linkage regions at 7q21.11, 9q22 and 16q24.1 in all families, and at 1q25.1, 1q25.3, 9q31.1-33.1, 9q33, 12p13.33, 15q11.2-13.3 and 16p12.3-12.2 in individual families replicate previous findings. High-resolution linkage mapping points to several novel candidate genes characterized by dense expression in the brain and potential impact on disorder-relevant synaptic transmission. Our study provides further evidence for common gene effects throughout different populations despite the complex multifactorial etiology of ADHD.

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Acknowledgements

We thank all families for their participation and support. We also greatly appreciate the support from several co-workers, who contributed to organization of the study, data management and technical assistance: Andrea Boreatti-Hümmer, Annette Nowak, Gabriela Ortega, Ulrike Schülter, Nicole Steigerwald, Theresia Töpner. We thank Professor Konstantin Strauch for supporting us in using the program GENEHUNTER-MODSCORE. This study was supported by the Deutsche Forschungsgemeinschaft (DFG: KFO 125, SFB 581, ME 1923/5-1, ME 1923/5-3, GRK 1389/1) and the Bundesministerium für Bildung und Forschung (BMBF: 01GV0605).

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Correspondence to M Romanos or K P Lesch.

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The authors declare no competing financial interests.

Author contributions: The study was supervised and directed by KPL, JM, CF and AW. MR, HP, CS and CJ ascertained and clinically characterized the families. JR, TR, MH and SW contributed to clinical characterization of family members. DWC, RB and DAS carried out the genetic analysis. Fine mapping was carried out by JS, CV and JM. Data analyses and genotyping were performed by KPL, MR, TR, AR and co-workers. Statistical analysis was performed by TN, AD and HS; CWK contributed to the power analysis. MR, CF, CJ and KPL wrote and revised the manuscript.

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Romanos, M., Freitag, C., Jacob, C. et al. Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Mol Psychiatry 13, 522–530 (2008). https://doi.org/10.1038/mp.2008.12

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