Genetic-epidemiological and biostatistical methods for clinical research on attention-deficit/hyperactivity disorder
Final Report Abstract
SP9 was responsible for the data management and the statistical support for the CRU 125. The focus was on the application of specific statistical methods for genetic epidemiology. Besides multiple candidate genes which were scanned for association with ADHD and concomitant diseases within large family and case-control-collectives, we performed a genome-wide linkage analysis by means of a dense marker system of 50 K SNP markers using 8 multi-generation pedigrees with 3 to 4 generations and 10 to 44 family members. For this, we applied advanced statistical methods such as MOD-Score analysis, a case only study analysing interactions of life events with serotonergic and dopaminergic ADHD candidate genes with respect to relevant comorbidity (gene environmental interactions). We took part in a meta-analysis of seven genome-wide linkage scans for ADHD as well as in a genome-wide association analysis by means of a 500 K SNP marker net using pooled DNA. Furthermore, the following statistical analyses were performed: meta-analyses to test for associations between tagging SNPs in multiple candidate genes and ADHD in four international large case-control-collectives using logistical regression models taking effects like centre effects into account; family-based association studies for qualitative and quantitative traits within a multi-generation family including several affected members, using a simulation procedure implemented in FBAT. By means of a genome-wide linkage analysis and association study but also in cooperation with other research groups, a large number of candidate genes were identified. Particularly, in genome-wide studies, evidence for an association of the DIRAS2 gene with ADHD was shown. In a meta-analysis of four large international case-control-samples which we performed in cooperation with an international group, ADHD associated SNP and haplotype variants on the promoter array of DIRAS2 were detected. We performed a gene-environment-interaction analysis and detected an interaction between a 5-HTTLPR polymorphism and life events with respect to Cluster B personality disorder, a comorbidity of adult ADHD. In a CNV scan we observed that the NPY duplication on chromosome segment 7p15 is found more frequently in ADHD- and obesity-affected members of an extended family and is associated with an increased NPY plasma concentration.
Publications
- (2008) Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Mol Psychiatry 13: 522-30
Romanos M, Freitag C, Jacob C, Craig DW, Dempfle A, Nguyen TT, Halperin R, Walitza S, Renner TJ, Seitz C, Romanos J, Palmason H, Reif A, Heine M, Windemuth-Kieselbach C, Vogler C, Sigmund J, Warnke A, Schäfer H, Meyer J, Stephan DA, Lesch KP
(See online at https://doi.org/10.1038/mp.2008.12) - (2008) Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm 115: 1573-85
Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Röser C, Nguyen TT, Craig DW, Romanos J, Heine M, Meyer J, Freitag C, Warnke A, Romanos M, Schäfer H, Walitza S, Reif A, Stephan DA, Jacob C
(See online at https://doi.org/10.1007/s00702-008-0119-3) - (2010) A gene-environment investigation on personality traits in two independent clinical sets of adult patients with personality disorder and attention deficit/hyperactive disorder. Eur Arch Psychiatry Clin Neurosci 260: 317-326
Jacob CP, Nguyen TT, Dempfle A, Heine M, Windemuth-Kieselbach C, Baumann K, Jacob F, Prechtl J, Wittlich M, Herrmann MJ, Gross-Lesch S, Lesch KP, Reif A
(See online at https://doi.org/10.1007/s00406-009-0079-0) - (2010) Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolescent Psychiatr 49: 884-97
Neale BM, Medland S, Ripke S, Asherson P, Franke B, Lesch KP, Faraone SV, Nguyen TT, Schäfer H, Holmans P, Daly M, Steinhausen HC, Freitag C, Reif A, Renner TJ, Romanos M, Romanos J, Walitza S, Warnke A, Meyer J, Palmason H, Buitelaar J, Vasquez AA, Lambregts- Rommelse N, Gill M, Anney RJ, Langely K, O'Donovan M, Williams N, Owen M, Thapar A, Kent L, Sergeant J, Roeyers H, Mick E, Biedermann J, Doyle A, Smalley S, Loo S, Hakonarson H, Elia J, Todorov A, Miranda A, Mulas F, Ebstein RP, Rothenberger A, Banaschewski T, Oades RD, Sonuga-Barke E, McGough J, Nisenbaum L, Middleton F, Hu X, Nelson S; Psychiatric GWAS Cosortium: ADHD Subgroup
(See online at https://doi.org/10.1016/j.jaac.2010.06.008) - (2011) DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders. Neuropsychopharmacology 36: 2318-2327
Reif A, Nguyen TT, Weissflog L, Jacob CP, Romanos M, Renner TJ, Buttenschon HN, Kittel- Schneider S, Gessner A, Weber H, Neuner M, Gross-Lesch S, Zamzow K, Kreiker S, Walitza S, Meyer J, Freitag CM, Bosch R, Casas M, Gomez N, Ribases M, Bayes M, Buitelaar JK, Kiemeney LA, Kooij JJ, Kan CC, Hoogman M, Johansson S, Jacobsen KK, Knappskog PM, Fasmer OB, Asherson P, Warnke A, Grabe HJ, Mahler J, Teumer A, Volzke H, Mors ON, Schafer H, Ramos-Quiroga JA, Cormand B, Haavik J, Franke B, Lesch KP
(See online at https://doi.org/10.1038/npp.2011.120) - (2011) Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene in an extended pedigree. Mol Psychiatry 16: 491-503
Lesch KP, Selch S, Renner TJ, Jacob C, Nguyen TT, Hahn T, Romanos M, Walitza S, Shoichet S, Dempfle A, Heine M, Boreatti-Hümmer A, Romanos J, Gross-Lesch S, Zerlaut H, Wultsch T, Heinzel S, Fassnacht M, Fallgatter A, Allolio B, Schäfer H, Warnke A, Reif A, Ropers HH, Ullmann R
(See online at https://doi.org/10.1038/mp.2010.29)
