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Studying the Biological Underpinnings of Quality of Life: Update on the GeneQol
Consortium Activities
Mirjam A.G. Sprangers, Melissa Thong and Jeff Sloan
ISOQOL, Miami, October 2013
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Co-Authors
Meike Bartels VU University, The Netherlands
Andrea Barsevick Thomas Jefferson University, USA
Juan Ordoñana University of Murcia, Spain
Qiuling Shi MD Anderson Cancer Center, University of Texas, USA
Shelley Wang MD Anderson Cancer Center, University of Texas, USA
Pål Klepstad St. Olav University Hospital, Norway
Eddy Wierenga University of Amsterdam, The Netherlands
Jasvinder Singh University of Alabama, USA
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Objectives
• To provide an update of the GeneQol Consortium activities
• To provide an updated overview of the biological pathways, candidate genes and molecular markers involved in QOL domains
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Objectives
• To provide an update of the GeneQol Consortium activities
• To provide an updated overview of the biological pathways, candidate genes and molecular markers involved in QOL domains
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Brief History
2009-date
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GENEQOL Consortium Interdisciplinary, International Network
Overall objectiveTo establish strong collaborative and interdisciplinary relationships to translate and conduct clinically relevant research to identify and investigate potential genes and genetic variants involved in QOL
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Translational Objective
Results of this work will enable providers to identify which patients are likely to experience symptoms and QOL deficits from disease and its treatments in order to:
– intervene prophylactically, – monitor patient well-being, – improve treatment decision-making, and– improve outcomes
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The Future?
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Clinical Implication
“Doctors will eventually use genetic patterns for several tasks -- to tell whether a cancer will spread, to predict how various therapies such as specific drugs or radiation will work, and perhaps even to see how someone's QOL will be affected.”(Sloan and Zhao, 2006)
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GENEQOL Consortium The Mayo Clinic/University of Amsterdam International Consortium for Genetics and Quality of Life Research
cellular biology molecular biologybehavioral genetics pharmacogeneticsbiological psychology nursingstatistical genetics sociologygenetic epidemiology psychiatrymedical psychology oncologyclinical psychology
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GENEQOL Consortium The Mayo Clinic/University of Amsterdam International Consortium
for Genetics and Quality of Life Research
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Meeting Objectives
• Develop a list of potential biological pathways, genes and genetic variants involved in QOL domains, by reviewing the state of the art regarding current genetic knowledge
• Design a research agenda to investigate and validate those genes and genetic variants of QOL
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Five Outcomes Under Study
• Negative emotional states (i.e. depression, anxiety)
• Positive emotional states (i.e. happiness, subjective wellbeing, life satisfaction)
• Perceived or self-rated physical health or functioning
• Pain• Fatigue
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Portfolio: Planned Papers
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Portfolio: Planned Papers
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Portfolio: Planned Papers
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Objectives
• To provide an update of the GeneQol Consortium activities
• To provide an updated overview of the biological pathways, candidate genes and molecular markers involved in QOL domains
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Objectives
• To provide an update of the GeneQol Consortium activities
• To provide an updated overview of the biological pathways, candidate genes and molecular markers involved in QOL domains: fatigue, pain, emotional functioning (depressed mood, well- being/happiness), social functioning, overall QOL
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Disclaimer
• The abundance of data in the literature is overwhelming
• This presentation is far from exhaustive
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Disclaimer
• The abundance of data in the literature is overwhelming
• This presentation is far from exhaustive• We present a selection of the most
interesting findings• Full paper is under review
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Literature Search
• Literature search in PubMed (2007-2012)• For pain and depressed mood: 2011-2012• Articles or book chapters found through
reference checking or personal communication (until June, 2013)
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Literature Search
• Literature search in PubMed (2007-2012)• For pain and depressed mood: 2011-2012• Articles or book chapters found through
reference checking or personal communication (until June, 2013)
• A gene or molecular marker is included if there is at least one publication (either empirical, meta-analysis or review) reporting its significant association with a QOL domain
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Candidate Gene Approach Hypothesis driven genetic marker selection, e.g.
based on expected biological pathway
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Candidate Gene Approach Hypothesis driven genetic marker selection, e.g.
based on expected biological pathway
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Candidate Gene Approach Hypothesis driven genetic marker selection, e.g.
based on expected biological pathway
Advantage:Knowledge- basedDisadvantage:May miss important genes
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Genome Wide Association Studies: GWAS Agnostic approach to examine genetic variants
across the whole genome
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Genome Wide Association Studies: GWAS Agnostic approach to examine genetic variants
across the whole genome
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Genome Wide Association Studies: GWAS Agnostic approach to examine genetic variants
across the whole genome
Advantage:Unexpected findingDisadvantage:Huge sample sizes
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Pain
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Candidate Gene Approach For Pain
COMT
Dopaminergic synapse
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Candidate Gene Approach For Pain
COMT 5HTT
Dopaminergic synapse
Serotonergic synapse
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Candidate Gene Approach For Pain
COMT OPRM15HTT
Dopaminergic synapse
Serotonergic synapse
Neuroactive ligand-receptor
interaction
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Candidate Gene Approach For Pain
SCN9ACOMT OPRM15HTT
Dopaminergic synapse
Serotonergic synapse
Neuroactive ligand-receptor
interaction
Sodium chemical
transporter
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Candidate Gene Approach For Pain: Conclusions
• Major pathways involved are related to: neurotransmission, inflammation, and response to analgesics
• COMT is associated with multiple sorts of pain
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GWAS For Pain
rs13361160
CREB
FAM119A
TCL1A
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GWAS For Pain
rs13361160
CREB
FAM119A
TCL1AChromosome 5p15.2
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GWAS For Pain: Conclusions
• Studies limited to single cohorts in specialized settings
• Identified gene candidates not intuitively biological plausible
• Inflammation and neuronal transmission are promising targets
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Depressed Mood
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GWAS for Depression
SP4
ATP6V1B
2
GRM7
rs161645
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GWAS for Depression: Conclusions
• A number of GWAS studies did not report any significant finding
• Results are inconclusive due to small effect sizes
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Candidate Gene Approach for Depression
• Numerous susceptible genes have been suggested without conclusive results
• One study reviewed and integrated 5,055 candidate genes, and ranked these based on magnitude of evidence (Kao et al, 2011)
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Candidate Gene Approach for Depression
DBH SLC6A4
Serotonergic pathway
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Candidate Gene Approach for Depression
GSK3BDBH BDNFSLC6A4 NGFR
Serotonergic pathway
Neurotrophin signalling pathway
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Candidate Gene Approach for Depression: Conclusions
• Neurotransmitter and neuroplasticity theories have the strongest evidence for their relationship with depressed mood.
• Further experiments and replication efforts are needed
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Wellbeing/Happiness
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Candidate Gene Approach For Well- Being/Happiness
5-HTT
Serotonergic synapse
MAOA
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GWAS For Well-Being/Happiness
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Well-being/Happiness: Conclusions
• Evidence that 5-10% of the variance in responses to questionnaires is accounted for by additive effects of SNPs (Rietveld et al., 2013)
• Large-scale genome-wide meta- analysis on > 100,000 genotyped individuals is underway
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Social Functioning
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Candidate Gene Approach For Social Functioning
OXTR
Neuroactive ligand receptor interaction
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Candidate Gene Approach For Social Functioning
OXTR HTR2A
Neuroactive ligand receptor interaction
Serotonergic synapse
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Candidate Gene Approach For Social Functioning
OXTR DRD4HTR2A MAO-A
Neuroactive ligand receptor interaction
Serotonergic synapse
Dopaminergic synapse
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GWAS For Social Functioning
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Social Functioning: Conclusions
• Most evidence for involvement of oxytocin-related genes
• Serotonergic and dopaminergic pathways are also important
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Summary
• There is promising evidence of genetic involvement in multiple QOL phenotypes through a variety of biological pathways
• This review provides a platform of the inclusion of pathways and genes/molecular markers in the design of future studies
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Discussion: Limitations
• Inclusion of any gene/molecular marker found significant at least once
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Discussion: Limitations
• Inclusion of any gene/molecular marker found significant at least once Ultimately, some genetic variables will fail to demonstrate a relationship with QOL
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Discussion: Limitations
• Inclusion of any gene/molecular marker found significant at least once Ultimately, some genetic variables will fail to demonstrate a relationship with QOL
• The number of genetic studies published to date varied widely across the different QOL domains
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Discussion: Limitations
• Inclusion of any gene/molecular marker found significant at least once Ultimately, some genetic variables will fail to demonstrate a relationship with QOL
• The number of genetic studies published to date varied widely across the different QOL domainsThere is a varied level of evidence for individual biomarker relationships
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Clinical Implications
• Ultimately, the goal of this research is to identify and use biological markers in clinical practice.
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Clinical Implications
• Ultimately, the goal of this research is to identify and use biological markers in clinical practice.
• Screening for predispositions to deficits in QOL holds the same clinical implications as screening for predispositions to disease and treatment outcomes.
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Clinical Implications
• Ultimately, the goal of this research is to identify and use biological markers in clinical practice.
• Screening for predispositions to deficits in QOL holds the same clinical implications as screening for predispositions to disease and treatment outcomes.
• For example, perhaps it is time to begin screening patients for cytokine markers to provide prophylactic interventions to prevent QOL deterioration, such as fatigue?