1. Power and limitations of GWAS Aaron Lorenz Department of Agronomy and Horticulture

2. Linkage versus association mapping Linkage mapping 1.Limited to two alleles per locus. a)QTL found limited to loci segregating between cross 2.Development of mapping populations required. 3.No family or population structure a)All individuals belong to same family and generation Association mapping 1.Many alleles segregating per locus. a)More loci segregating 2.Any genetically diverse natural or artificial population can be used (germplasm bank accessions, breeding lines, collection of cultivars). 3.Often severe population structure and differential kinship among individuals

3. Power versus false-discovery rate False positives True positives True negatives False negatives No linked QTLLinked QTL Fail to reject H 0 Reject H 0 β = Fail to reject null hypothesis given it is false (e.g., there is a linked QTL). Power = 1 - β False discovery rate = probability null hypothesis is true even though it has been rejected (e.g., QTL declared in absence of true QTL). Bernardo (2010)

4. Drawbacks Inadequate marker density -> Low power Make sure enough markers are used so that there is adequate LD between markers (and therefore between markers and QTL). Power to detect QTL strongly related to amount variation explained by nearby marker. Amount of variation explained by nearby marker is product of QTL size and marker-QTL LD.

5. Power to detect QTL is function of phenotypic variance generated by QTL

6. Drawbacks: Low minor-allele frequency Myles et al. (2009)

7. Drawbacks: Adjusting for population structure reduces power ( by statistically removing the variation generated by that QTL ) Minor-allele frequency Fst Power Rincent et al. (2014)

8. Drawbacks: High statistical threshold to account for multiple testing Gibson (2010)

9. Maher (2008)

10. TraitNumber of loci%h2 explained Crohn’s disease3220 Lupus615 Type 2 diabetes186 HDL cholesterol75.2 Height405 Myocardial infarction 92.8 Fasting glucose41.5 Manolio et al. (2009)

12. References Bernardo, R. 2010. Breeding for quantitative traits in plants. Stemma Press, Woodbury, MN. Gibson, G. 2010. Hints of hidden heritability in GWAS. Nat. Genet. 42:558- 560. Maher, B. 2008. The case of the missing heritability. Nature 456:18-21. Manolio, T.A., F.S. Collins, N.J. Cox, D.B. Goldstein, L.A. Hindorff, D.J. Hunter, M.I. McCarthy, E.M. Ramos, L.R. Cardon and A. Chakravarti. 2009. Finding the missing heritability of complex diseases. Nature 461:747-753. Myles, S., J. Peiffer, P.J. Brown, E.S. Ersoz, Z. Zhang, D.E. Costich and E.S. Buckler. 2009. Association mapping: Critical considerations shift from genotyping to experimental design. Plant Cell 21:2194-2202. Rincent, R., L. Moreau, H. Monod, E. Kuhn, A.E. Melchinger, R.A. Malvar, J. Moreno-Gonzalez, S. Nicolas, D. Madur, V. Combes, F. Dumas, T. Altmann, D. Brunel, M. Ouzunova, P. Flament, P. Dubreuil, A. Charcosset and T. Mary- Huard. 2014. Recovering power in association mapping panels with variable levels of linkage disequilibrium. Genetics 197:375-387.