title: Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships.
abstract: There is growing interest in the role of rare variants in the variation of complex traits due to increasing evidence that rare variants are associated with quantitative traits. However, association methods that are commonly used for mapping common variants are not effective to map rare variants. Besides, livestock populations have large half-sib families and the occurrence of rare variants may be confounded with family structure, which makes it difficult to disentangle their effects from family mean effects. We compared the power of methods that are commonly applied in human genetics to map rare variants in cattle using whole-genome sequence data and simulated phenotypes. We also studied the power of mapping rare variants using linear mixed models (LMM), which are the method of choice to account for both family relationships and population structure in cattle.
  
  
  
  We observed that the power of the LMM approach was low for mapping a rare variant (defined as those that have frequencies lower than 0.01) with a moderate effect (5 to 8 % of phenotypic variance explained by multiple rare variants that vary from 5 to 21 in number) contributing to a QTL with a sample size of 1000. In contrast, across the scenarios studied, statistical methods that are specialized for mapping rare variants increased power regardless of whether multiple rare variants or a single rare variant underlie a QTL. Different methods for combining rare variants in the test single nucleotide polymorphism set resulted in similar power irrespective of the proportion of total genetic variance explained by the QTL. However, when the QTL variance is very small (only 0.1 % of the total genetic variance), these specialized methods for mapping rare variants and LMM generally had no power to map the variants within a gene with sample sizes of 1000 or 5000.
  
  
  
  We observed that the methods that combine multiple rare variants within a gene into a meta-variant generally had greater power to map rare variants compared to LMM. Therefore, it is recommended to use rare variant association mapping methods to map rare genetic variants that affect quantitative traits in livestock, such as bovine populations.
authors.affiliation: Department of Molecular Biology and Genetics, Center for Quantitative Genetics and Genomics, Aarhus University, Tjele, 8830, Denmark. qianqian.zhang@mbg.au.dk.|Animal Breeding and Genomics Centre, Wageningen UR Livestock Research, Wageningen, The Netherlands. qianqian.zhang@mbg.au.dk.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology and Genetics, Center for Quantitative Genetics and Genomics, Aarhus University, Tjele, 8830, Denmark.
authors.forename: Bernt
authors.initials: B
authors.lastname: Guldbrandtsen
authors.affiliation: Animal Breeding and Genomics Centre, Wageningen UR Livestock Research, Wageningen, The Netherlands.
authors.forename: Mario P L
authors.initials: MP
authors.lastname: Calus
authors.affiliation: Department of Molecular Biology and Genetics, Center for Quantitative Genetics and Genomics, Aarhus University, Tjele, 8830, Denmark.
authors.forename: Mogens Sandø
authors.initials: MS
authors.lastname: Lund
authors.affiliation: Department of Molecular Biology and Genetics, Center for Quantitative Genetics and Genomics, Aarhus University, Tjele, 8830, Denmark.
authors.forename: Goutam
authors.initials: G
authors.lastname: Sahana
mesh_terms: D000818:Animals; D002417:Cattle / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D014644:Genetic Variation; D005838:Genotype; D016014:Linear Models; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable