Richa Gupta's dissertation demonstrates the interplay between the genome and epigenome in smoking

The main aim of M.Sc. Richa Gupta’s thesis entitled "Association and interplay of genetic and epigenetic variants in smoking behavior” was to identify genetic and epigenetic alterations affecting smoking behaviour and to understand their interplay.

Smoking is the single greatest preventable cause of death in the world today and thus extremely relevant research topic from the public health perspective. Understanding the consequences and mechanisms involved in smoking behaviour is the key for providing personalised treatment to support smoking cessation.

In her thesis work, M.Sc. Richa Gupta has focused on studying the links between the smoking behaviour and genetic as well as epigenetic variation. Her doctoral dissertation will be publically examined on Friday, 20 April, with the permission of the Faculty of Medicine of the University of Helsinki.

Richa Gupta graduated from the King’s College London in 2012, with a masters in bioinformatics. Her bachelors was in biotechnology giving her a good understanding of both computational and laboratory aspects of research.  In 2013, she got a highly competitive scholarship for a Marie Curie position in Jaakko Kaprio’s research group at the Department of Public Health and moved to Finland to start her PhD project.

Richa’s thesis project is part of Jaakko Kaprio’s Finnish Twin Cohort project entity. Professor Kaprio and Dr. Miina Ollikainen are the official supervisors of the thesis and Dr. Anu Loukola has contributed significantly to each of the studies.

In her thesis study, Richa has focused on identifying novel associations and validating the involvement of known candidate genes in smoking behaviour. She has utilised several different omics data, including genetics (assessed by single nucleotide polymorphisms), epigenetics (assessed by DNA methylation), as well as transcriptomics data. This has allowed her to assess the functional implications of the genetic associations identified.

The integrative analysis using expression and DNA methylation data that we employed to uncover the regulatory potential of variants associated with smoking behaviour phenotypes has been the corner stone of this thesis.

- Richa Gupta

The thesis consists of three publications, two of which have already been published and one is under review. In all of the studies, twin cohorts have been used, while also other Finnish study samples have been analysed.

In the first publication of the thesis, the team performed a first ever genome-wide association study using nicotine metabolites measured from the serum - instead of questionnaire-based data - as the smoking behaviour phenotype. The results of this study showed that variants in or near the CYP2A6 gene explain a large proportion of variance in nicotine metabolism rate.

Our results were also interesting from the translational point of view, as nicotine metabolism rate has been shown to influence the efficacy of smoking cessation pharmacotherapies. Genetic profile focusing on the most significantly associated SNPs can be of great utility in clinical settings to personalise cessation therapeutics.

In the second publication, Richa wanted to identify epigenetically regulated smoking-related genes. She performed an epigenome-wide association study using serum cotinine levels, a reliable indicator of nicotine exposure as opposed to error-prone self-reported smoking. When the identified methylation changes were further evaluated, a few were shown not to be a direct consequence of nicotine exposure but rather a mediator between the observed association of genotype and cotinine levels.

In the last study, Richa validated the role of neuregulin signalling pathway genes in smoking behaviour. Utilising integrative methods and multi-omics data, she was able to highlight regulatory potential in most of the associated variants.

My thesis highlights the importance of using multiple biological data layers when the goal is to assess the regulatory potential of seemingly non-functional genetic variation. Our findings suggest that the genome and the epigenome act in concert and methylation may be a molecular mechanism mediating the observed effects in at least some of the highlighted genes.

When asked about the keys to a successful thesis project, Richa leverages her ability to bring laughter into her life and her hyper-organised nature. In her free time, she really enjoys traveling.

Richa wants to thank her supervisors, Anu Loukola and all her colleagues from the Kaprio and Ollikainen teams for providing such a supportive and enjoyable working environment. She will continue her research career in the US, where she will soon move to.

The public examination of Richa Gupta’s doctoral dissertation will take place on 20 April at 12 o'clock noon in Seminar room 3 at Biomedicum Helsinki 1, Haartmaninkatu 8. The thesis has been supervised by FIMM Group Leaders, Professor Jaakko Kaprio and Dr. Miina Ollikainen (University of Helsinki). Associate Professor Bas Heijmans (Leiden University Medical Center, Netherlands) will serve as the opponent and Professor Jaakko Kaprio as the custos. The dissertation is also available in an electronic form.