Association mapping of insecticide resistance in wild Anopheles gambiae populations: major variants identified in a low-linkage disequilbrium genome.
BACKGROUND
Association studies are a promising way to uncover the genetic basis of complex traits in wild populations. Data on population stratification, linkage disequilibrium and distribution of variant effect-sizes for different trait-types are required to predict study success but are lacking for most taxa. We quantified and investigated the impacts of these key variables in a large-scale association study of a strongly selected trait of medical importance: pyrethroid resistance in the African malaria vector Anopheles gambiae.


RESULTS
We genotyped ≈1500 resistance-phenotyped wild mosquitoes from Ghana and Cameroon using a 1536-SNP array enriched for candidate insecticide resistance gene SNPs. Three factors greatly impacted study power. (1) Population stratification, which was attributable to co-occurrence of molecular forms (M and S), and cryptic within-form stratification necessitating both a partitioned analysis and genomic control. (2) All SNPs of substantial effect (odds ratio, OR>2) were rare (minor allele frequency, MAF<0.05). (3) Linkage disequilibrium (LD) was very low throughout most of the genome. Nevertheless, locally high LD, consistent with a recent selective sweep, and uniformly high ORs in each subsample facilitated significant direct and indirect detection of the known insecticide target site mutation kdr L1014F (OR≈6; P<10(-6)), but with resistance level modified by local haplotypic background.


CONCLUSIONS
Primarily as a result of very low LD in wild A. Gambiae, LD-based association mapping is challenging, but is feasible at least for major effect variants, especially where LD is enhanced by selective sweeps. Such variants will be of greatest importance for predictive diagnostic screening.
Vector Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom. dweetman@liv.ac.uk
David
D
Weetman
Craig S
CS
Wilding
Keith
K
Steen
John C
JC
Morgan
Frédéric
F
Simard
Martin J
MJ
Donnelly
D000818:Animals; D000852:Anopheles / Q000235:genetics*; D002163:Cameroon; D005869:Ghana; D006239:Haplotypes; D007305:Insecticide Resistance / Q000235:genetics*; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D015222:Sodium Channels / Q000235:genetics
D015222:Sodium Channels