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Genetics. 2019 Oct;213(2):633-650. doi: 10.1534/genetics.119.302381. Epub 2019 Aug 27.

Genetic Signatures of Drug Response Variability in Drosophila melanogaster.

Author information

1
Center for Quantitative Genetics and Genomics, Department of Molecular Biology and Genetics, Aarhus University, 8830 Tjele, Denmark palle.d.rohde@mbg.au.dk.
2
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8000 Aarhus C, Denmark.
3
Center for Integrative Sequencing, Aarhus University, 8000, Denmark.
4
Section for Biology and Environmental Science, Department of Chemistry and Bioscience, Aalborg University, 9220, Denmark.
5
Center for Quantitative Genetics and Genomics, Department of Molecular Biology and Genetics, Aarhus University, 8830 Tjele, Denmark.
6
Department of Biomedicine, Aarhus University, 8000, Denmark.
7
Section for Genetics, Ecology and Evolution, Department of Bioscience, Aarhus University, 8000, Denmark.

Abstract

Knowledge of the genetic basis underlying variation in response to environmental exposures or treatments is important in many research areas. For example, knowing the set of causal genetic variants for drug responses could revolutionize personalized medicine. We used Drosophila melanogaster to investigate the genetic signature underlying behavioral variability in response to methylphenidate (MPH), a drug used in the treatment of attention-deficit/hyperactivity disorder. We exposed a wild-type D. melanogaster population to MPH and a control treatment, and observed an increase in locomotor activity in MPH-exposed individuals. Whole-genome transcriptomic analyses revealed that the behavioral response to MPH was associated with abundant gene expression alterations. To confirm these patterns in a different genetic background and to further advance knowledge on the genetic signature of drug response variability, we used a system of inbred lines, the Drosophila Genetic Reference Panel (DGRP). Based on the DGRP, we showed that the behavioral response to MPH was strongly genotype-dependent. Using an integrative genomic approach, we incorporated known gene interactions into the genomic analyses of the DGRP, and identified putative candidate genes for variability in drug response. We successfully validated 71% of the investigated candidate genes by gene expression knockdown. Furthermore, we showed that MPH has cross-generational behavioral and transcriptomic effects. Our findings establish a foundation for understanding the genetic mechanisms driving genotype-specific responses to medical treatment, and highlight the opportunities that integrative genomic approaches have in optimizing medical treatment of complex diseases.

KEYWORDS:

ADHD; Drosophila Genetic Reference Panel; Ritalin; cross-generational effects; locomotor activity

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