Overview1. What are single nucleotide polymorphisms (SNPs)?
1.1 SNP and disease-causing mutations: the same?
1.2 How SNPs are detected?
1.3 What can we do with the SNPs data?
2. GWAS: Genome-Wide Association Study
2.1 GWAS Catalog
3. Complex traits and diseases
3.1 Complex traits and diseases: heritability
3.2 Studying the heritability of complex traits with GWAS
3.3 Multi-stage disease model
3.4 The role of epistasis in complex traits
4. Concluding remarks
5. References
What are single nucleotide polymorphisms (SNPs)?• Single-nucleotide substitutions of one base for
another
• 84,7M SNP (88M variants, The 1000 Genome
Project Consortium, 1 October 2015)
• Most common type of genetic variation
(polymorphism) among individuals
• Goal: Identify SNP correlated with particular
effects in patients.
1
(8 Haplotypes)
Making SNPs Make
Sense. Retrieved
December 7, 2015,
from
http://learn.genetics.
utah.edu/content/ph
arma/snips/
‒ Biomarkers of specific diseases → Asses risk!
‒ Effectiveness of a drug/s
‒ Susceptibility to environmental factors.
‒ Adverse effects of a given drug
SNP and disease-causing mutations: the same?1.1
(8 Haplotypes)
• SNP ≠ disease-causing mutation → point mutations
• SNP are present in at least 1% of the general
population
• Most disease-causing mutations occur within a
coding or regulatory region of a gene affecting the
function of the protein
Any disease-causing mutation is this common
SNP are not
necessarily located
within genes
Two main
categories
Making SNPs Make Sense. Retrieved December 7, 2015, from
http://learn.genetics.utah.edu/content/pharma/snips/
rSNP or
srSNPs
cSNP
How SNPs are detected?
• SNP genotyping: determine the number of SNP in a DNA fragment by examining
the DNA with several methods and comparing it with a reference sequence
1.2
Chen, X., & Sullivan, P. F. (2003). Single nucleotide polymorphism
genotyping: biochemistry, protocol, cost and throughput. The
Pharmacogenomics Journal, 3(2), 77–96. http://doi.org/10.1038/sj.tpj.6500167
Making SNPs Make Sense. Retrieved December 7, 2015,
from http://learn.genetics.utah.edu/content/pharma/snips/
Different
approaches:
Low - high
throughput (next
generation
sequencing)
The scale of the
genotyping and
the cost defines
the study design
SNPs are sorted and
catalogued in databases
(dbSNP, HapMap
project, 1000 Genomes
project…) → rs number
What can we do with the SNPs data?1.3
GWAS
Genomic data
SNPs are associated to
a function or response
Phenotypic data
GWAS: Genome-Wide Association Study• Developed in 2007
• Based on the concept that genetic variation shows considerable linkage
disequilibrium → A given SNP is strongly correlated with other SNPs
• GWAS tests a single Tag SNP from regions of LD to mark the zones in the
genome showing disease association
2
Co-inherited more often than
expected by random events
In a typical study →500K-1000K SNPs are tested → 0,6 – 1,2% of the SNPs already known in
the human genome (2015, 1000 Genome Project) → SNP accepted = p-value ≤ 5.0 × 10-8
Gibson, G. (2010). Hints of hidden heritability in GWAS. Nature Genetics, 42(7),
558–60. http://doi.org/10.1038/ng0710-558
Problem?
GWAS Catalog2.1
All SNP-trait associations with
p-value ≤ 5.0 × 10-8, published
in the GWAS Catalog
GWAS Catalog. Retrieved December 8,
2015, from https://www.ebi.ac.uk/gwas/
5267 SNP-trait associations
Complex traits and diseases3
• The vast majority of diseases complex:
Environmental and genetic interactions (2015). Retrieved from
http://www.genetics.edu.au/Publications-and-Resources/Genetics-Fact-Sheets/
Complex traits and diseases: heritability3.1
• Despite the polygenic feature, heritability in several common diseases can be explained
Sadee, W., Hartmann, K., Seweryn, M., Pietrzak, M., Handelman, S. K., & Rempala, G. A. (2014). Missing heritability of common diseases and treatments outside the
protein-coding exome. Human Genetics, 133(10), 1199–215. http://doi.org/10.1007/s00439-014-1476-7
Studying the heritability of complex traits with GWAS
• Genomics of complex disease remains unresolved
• Genetic factors identified only explain a small portion of heritability estimation → Height
• Only 20% of estimated heritability explained by the combination of all significant SNPs →
SNPs with small individual effects/ low frequent hidden in GWAS
• Heritability can be defined in two ways
3.2
Missing/hidden heritability
h2
H2
Additive effect of individual alleles
Epistasis + epigenetics
5% (50 SNPs)
Multi-stage disease model3.3
Sadee, W., Hartmann, K., Seweryn, M., Pietrzak, M., Handelman, S. K., & Rempala, G. A. (2014). Missing heritability of common diseases and treatments outside the
protein-coding exome. Human Genetics, 133(10), 1199–215. http://doi.org/10.1007/s00439-014-1476-7
(positive selection) (subclinical state) (clinical non-
measurable state )
(clinical measurable
state)
rSNPHigh/low activity SNPs
The role of epistasis in complex traits3.4
• Interactions gene-gene-environment
Epistasis
Non-linear gene-gene-environment interactions
Interactions between SNPs in the same gene
SNPBeneficial
Deleterious
Phenotype
Environment
2nd mutation
Complex traits
Complex diseases
Interactions
DRD2/DAT
DRD2 (Dopamine D2 receptor):
Splicing SNP increases (3X)
lethal risk of cocaine abuse
DAT (dopamine transporter):
variants with no effects
2 interactions
7-8X increased
lethal risk of
cocaine abuse
Total compensation
of the disease risk
Explains missing heritability GWAS issues Wellcome Trust Study
Concluding remarks4
• GWAS studies need to focus on the role of causative SNP, not only on marker SNP
• Redefine GWAS studies with larger number of cases and a different treshold to look for
rare SNPs
• Better study of rSNP and its role affecting epigenetic DNA and chromatin marks → Better
understanding of epigenetics
• SNPs positive selected could cause deleterious effects under certain conditions →
Undetected to GWAS (low score) → Better study of epistasis phenomena
• How can we quantify the effect of environment on human health?
• Cost of sequencing is steadily decreasing → Sequencing more individuals → more SNP
data of both common and rare SNPs
• Re-estimate heritability to contemplate the effects of environment, epigenetics, epistasis…
Unknown in the majority of casesGain or loss of function?
References• Making SNPs Make Sense. Retrieved December 7, 2015, from http://learn.genetics.utah.edu/content/pharma/snips/
• GWAS Catalog. Retrieved December 8, 2015, from https://www.ebi.ac.uk/gwas/
• What are single nucleotide polymorphisms (SNPs)? (2015). Retrieved from http://ghr.nlm.nih.gov/handbook/genomicresearch/snp
• What are complex or multifactorial disorders? (2015). Retrieved from
http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/complexdisorders
• Environmental and genetic interactions (2015). Retrieved from http://www.genetics.edu.au/Publications-and-Resources/Genetics-
Fact-Sheets/
• Nickerson, D. Overview of SNP Genotyping. Retrieved December 9, 2015, from
https://www.niehs.nih.gov/news/assets/docs_p_z/snp_genotyping_508.pdf
• Chen, X., & Sullivan, P. F. (2003). Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput.
The Pharmacogenomics Journal, 3(2), 77–96. http://doi.org/10.1038/sj.tpj.6500167
• Auton, A., Abecasis, G. R., Altshuler, D. M., Durbin, R. M., Bentley, D. R., Chakravarti, A., … Schloss, J. A. (2015). A global reference
for human genetic variation. Nature, 526(7571), 68–74. http://doi.org/10.1038/nature15393
• Atanasovska, B., Kumar, V., Fu, J., Wijmenga, C., & Hofker, M. H. (2015). GWAS as a Driver of Gene Discovery in Cardiometabolic
Diseases. Trends in Endocrinology and Metabolism: TEM, 26(12), 722–732. http://doi.org/10.1016/j.tem.2015.10.004
• Sadee, W., Hartmann, K., Seweryn, M., Pietrzak, M., Handelman, S. K., & Rempala, G. A. (2014). Missing heritability of common
diseases and treatments outside the protein-coding exome. Human Genetics, 133(10), 1199–215. http://doi.org/10.1007/s00439-
014-1476-7
• Donnelly, P. (2008). Progress and challenges in genome-wide association studies in humans. Nature, 456(7223), 728–31.
http://doi.org/10.1038/nature07631
• Maher, B. (2008). Personal genomes: The case of the missing heritability. Nature, 456(7218), 18–21.
http://doi.org/10.1038/456018a
• Gibson, G. (2010). Hints of hidden heritability in GWAS. Nature Genetics, 42(7), 558–60. http://doi.org/10.1038/ng0710-558
5
THANK YOU VERY MUCH FOR YOUR
ATTENTION!
Hidden or
missing
heritability?