Functional molecular genetics: genotype-phenotype correlation and linkage analysis in attention-deficit/hyperactivity disorder
Zusammenfassung der Projektergebnisse
The activities of SP3 focused on several objectives: Association studies on known and novel candidate genes using the cohorts recruited by SP1 and 2 were performed using populationand family-based designs. In collaboration with SP6, 7, 8, and 10 (JRG) genotyping was carried out to detect the relationship between genetic polymorphisms and neurophysiological and neuropsychological functionality and neuronal activation in fMRI. Several external collaborations have been started to use synergisms and accelerate progress. Further finemapping on the multigenerational families and the family sample recruited by SP1 was done in M. Muenke’s laboratory at the National Human Genome Research Institute, NIH, Bethesda. Markers define a chromosomal locus at 4q13.2, previously reported as a relevant region by a genome-wide linkage scan. To improve power, the samples recruited in Homburg and Trier have also been included in this finemapping attempt. First analyses indicate replication of the previous finding and a common haplotype (frequency, 22.2%) within the gene encoding Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, was found in LD to ADHD (P < 2.7 x 10^-5). ADHD susceptibility haplotype variants reconstructed from 23 additional markers, iteratively validated the presence of the core haplotype in our ADHD familial sample (n=244, P<3.8 x 10^-5) with a Ppooled< 3.01 x 10^-8 (RR 2.6). Variants complementary to the susceptibility haplotype confer protection against ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopaminepositive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, these results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry. In collaborations with the National Institute of Child Health and Human Development (NICHHD), Bethesda, the influence of genetic polymorphisms on emotionality and development of macaques has been investigated. The primary focus has been the susceptibility to disorders due to early adversity. An impact of the promoter variant of monoamine oxidase A (MAOA) on the development of macaques being exposed to early adversity was found. By sequential analysis the prevalence a VNTR homolog to the known VNTR in humans was shown in several nonhuman primates species, providing the basis for studies on aggressive traits in these primates. Results of investigation on MAOA, SLC6A4, DRD4, and DAT suggest a role of MAOA and SLC6A4 in impulsive/aggressive traits. In collaboration with H.H. Ropers and colleagues at the Max Planck Institute for Molecular Genetics, Berlin, 100 children recruited by SP1 have been included in a sample being tested by a high-resolution microarray-based Comparative Genomic Hybridization (arrayCGH). The study sample was designed to include two subtypes of patients: Either these children were the only ones affected by ADHD in their families with potential de novo alterations, or they feature a very high rate of familiarity descending of multigenerational families. The sexmatched control groups comprised DNA of 50 males and females. Preliminary analyses of the arrayCGH data indicate chromosomal alterations in several probands, including a duplication on chromosome 7p segregating with the ADHD phenotype in a large multigenerational pedigree).
Projektbezogene Publikationen (Auswahl)
- (2005) Monoamine oxidase A gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys. Biol Psychiatry 57: 167-172
Newman TK, Syagailo YV, Barr CS, Wendland JR, Champoux M, Graessle M, Suomi SJ, Higley JD, Lesch KP
(Siehe online unter https://doi.org/10.1016/j.biopsych.2004.10.012) - (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10: 1126-1132
Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A, Herpertz-Dahlmann B, Remschmidt H, Smidt J, Linder M, Flierl L, Knolker U, Friedel S, Schafer H, Gross C, Hebebrand J, Warnke A, Lesch KP
(Siehe online unter https://doi.org/10.1038/sj.mp.4001734) - (2008) Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Mol Psychiatry 13: 522-530
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, Schafer H, Meyer J, Stephan DA, Lesch KP
(Siehe online unter https://doi.org/10.1038/mp.2008.12) - (2010) A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry 15: 1053-1066
Arcos-Burgos M, Jain M, Acosta MT, Shively S, Stanescu H, Wallis D, Domene S, Velez JI, Karkera JD, Balog J, Berg K, Kleta R, Gahl WA, Roessler E, Long R, Lie J, Pineda D, Londono AC, Palacio JD, Arbelaez A, Lopera F, Elia J, Hakonarson H, Johansson S, Knappskog PM, Haavik J, Ribases M, Cormand B, Bayes M, Casas M, Ramos-Quiroga JA, Hervas A, Maher BS, Faraone SV, Seitz C, Freitag CM, Palmason H, Meyer J, Romanos M, Walitza S, Hemminger U, Warnke A, Romanos J, Renner T, Jacob C, Lesch KP, Swanson J, Vortmeyer A, Bailey-Wilson JE, Castellanos FX, Muenke M
(Siehe online unter https://doi.org/10.1038/mp.2010.6) - (2011) Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage 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-Hummer A, Romanos J, Gross-Lesch S, Zerlaut H, Wultsch T, Heinzel S, Fassnacht M, Fallgatter A, Allolio B, Schafer H, Warnke A, Reif A, Ropers HH, Ullmann R
(Siehe online unter https://doi.org/10.1038/mp.2010.29) - (2012) Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry 169: 195-204
Williams NM, Franke B, Mick E, Anney RJ, Freitag CM, Gill M, Thapar A, O'Donovan MC, Owen MJ, Holmans P, Kent L, Middleton F, Zhang-James Y, Liu L, Meyer J, Nguyen TT, Romanos J, Romanos M, Seitz C, Renner TJ, Walitza S, Warnke A, Palmason H, Buitelaar J, Rommelse N, Vasquez AA, Hawi Z, Langley K, Sergeant J, Steinhausen HC, Roeyers H, Biederman J, Zaharieva I, Hakonarson H, Elia J, Lionel AC, Crosbie J, Marshall CR, Schachar R, Scherer SW, Todorov A, Smalley SL, Loo S, Nelson S, Shtir C, Asherson P, Reif A, Lesch KP, Faraone SV
(Siehe online unter https://doi.org/10.1176/appi.ajp.2011.11060822) - (2012) Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 44: 78-84
Elia J, Glessner JT, Wang K, …, Reif A, Rothenberger A, Franke B, Mick EO, Roeyers H, Buitelaar J, Lesch KP, Banaschewski T, Ebstein RP, Mulas F, Oades RD, Sergeant J, Sonuga- Barke E, Renner TJ, Romanos M, Romanos J, Warnke A, Walitza S, Meyer J, Pálmason H, Seitz C, Loo SK, Smalley SL, Biederman J, Kent L, Asherson P, Anney RJL, Gaynor JW, Shaw P, Devoto M, White PS, Grant SFA, Buxbaum JD, Rapoport JL, Williams NM, Nelson SF, Faraone SV, Hakonarson H
(Siehe online unter https://doi.org/10.1038/ng.1013) - (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45: 984-94
Cross-Disorder Group of the Psychiatric Genomics Consortium, Lee SH, Ripke S, Neale BM, Faraone SV, …, Lesch KP, …, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR
(Siehe online unter https://dx.doi.org/10.1038%2Fng.2711) - (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381: 1371-1379
Cross-Disorder Group of the Psychiatric Genomics Consortium, Smoller JW, Craddock N, Kendler K, Lee PH, Neale BM, Nurnberger JI, Ripke S, Santangelo S, Sullivan PF, … Lesch KP, …, Craddock N, Kendler K
(Siehe online unter https://doi.org/10.1016/S0140-6736(12)62129-1)
