genetic diversity: pitfalls and benefits (2013)
TRANSCRIPT
Genetic diversity: pitfalls and benefits
Peter Kamerman
4th International Congress on Neuropathic Pain, Toronto, Canada, 2013
PaleoPlaybook
Population-based genetic variation
Tishkoff and Williams, 2002
Population-based genetic variation
Founder effect
Adapted from: Li et al., 2008
POPULATION-BASED GENETIC VARIATION
Population-based genetic variation
GENETIC ASSOCIATION STUDIES
Population-based genetic variation
Is there an association between allele
frequency and presence of a trait?
Marker polymorphisms
Causative polymorphisms
(e.g., single nucleotide polymorphisms - SNPs)
Trait variability
CONSEQUENCES OF GENETIC DIVERSITY
Population-based genetic variation
Differences in allele frequency
Differences in linkage disequilibrium
Differences in trait frequency
DIFFERENCES IN ALLELE FREQUENCY
KCNS1 – rs734784
Population-based genetic variation
DIFFERENCES IN ALLELE FREQUENCY
Population-based genetic variation
KCNS1 – rs734784
SPSmart v5.1.1; 1000 Genomes Phase I
T C C TT
C
Adapted from Tegeder et al., 2006
SNPsH
aplo
type
s
Ancestral
Recombination
10 generations
20 generations
Recombination
Stre
ngth
of L
D
DIFFERENCE IN LINKAGE DISEQUILIBRIUM (LD)
Population-based genetic variation
Adapted from McVean et al., 2005
Rec
ombi
natio
n ho
tspo
ts
Africa (YRI)
Position on chromosome
White (CEU)
Asian (CHN)
DIFFERENCES IN LINKAGE DISEQUILIBRIUM (LD)
Population-based genetic variation
ENCODE regionChromosome 7q31.33
European (CEU)• 25 SNPs MAF > 0.1
• 8 tagSNPs (r2 >0.8)
GTP CYCLOHYDROLASE GENE (GCH1) TAGSNPS
Population-based genetic variation
African (YRI)• 32 SNPs MAF > 0.1
• 19 tagSNPs (r2 >0.8)
GTP CYCLOHYDROLASE GENE (GCH1) TAGSNPS
Population-based genetic variation
DIFFERENCES IN LD?
Population-based genetic variation
KCNS1 – rs734784
158 Black African patients with HIV-SN
•Literature-based SNP selection
•Population-based tagSNP selection(HapMap #27, YRI, pairwise tagging, r2 = 1, MAF > 0.01)
DIFFERENCES IN LD?
Population-based genetic variation
KCNS1
Hendry et al., 2013
4 SNPs- 3 TagSNPs (PURPLE)- 1 Literature (GREEN)
KCNS1
DIFFERENCES IN LD?
Population-based genetic variation
Hendry et al., 2013
KCNS1
Population-based genetic variation
ONLY TAGSNP HAPLOTYPES ASSOCIATE WITH CHANGES IN PAIN INTENSITY
Population-based genetic variation
Palmer and Cardon, 2005
Population-based genetic variation
Palmer and Cardon, 2005
Adapted from Palmer and Cardon, 2005
High LD: European
Low LD: African
Multi-cohort studiesP
ower
(%)
Sample size (cases)
Relative risk: 1.5LD: r2 =0.9Disease prevalence: 20%
MAF:
4%
3%
2%
1%
5%
Population structure
Marchini et al., 2004
Population stratification
A POSSIBLE WHEN ASSESSING GENETIC RISK OF HIV-SN
RSA: 37-58%
Uganda: 47%
Malawi: 35-56%
South-East Asia : 10-34%
Population structure
A POSSIBLE PROBLEM WHEN ASSESSING GENETIC RISK OF HIV-SN
Malawi: Beadles et al., 2009; van Oosterhout et al., 2005; South Africa: Hitchcock et al., 2008; Maritz et al., 2010; Wadley et al., 2011; SE Asia: Affandi et al., 2008; Sithinamsuwan et al., 2008; Vivithanaporn et al., 2010; Wright et al., 2008; Uganda: Nakasujja et al., 2005
Population structure
A POSSIBLE PROBLEM WHEN ASSESSING GENETIC RISK OF HIV-SN
SE Asia: Affandi et al., 2008; South Africa: Wadley et al., unpublished data
T
C
T
C
TNFA – rs1799964
> SN risk:✗ > SN risk:✓
Population structure
Discrete: Populations that are remotely related
Admixed: Admixed ancestry
Hierarchical: Both discrete and admixed population structures.
TYPES OF POPULATION STRUCTURE
Population stratification
METHODS FOR CORRECTING FOR POPULATION STRUCTURE
Family-based study designs
Null-marker designs:Structured association
Principal components analysis
Population-based genetic variation
Adapted from Palmer and Cardon, 2005
-Log
10(P
val
ue)
Chromosome position
BENEFITS OF GENETIC DIVERSITY
And finally,
The three most important issues in genetic association studies are…
Phenotype
Phenotype
Phenotype