β-composite Interval Mapping for robust QTL analysis

Abstract

Interval mapping approaches have been playing significant role for quantitative trait locus (QTL) mapping to discover genetic architecture of diseases or traits with molecular markers. Composite interval mapping (CIM) is one of the superior approaches of the interval mapping for discovering both linked and unlinked putative QTL positions. However, estimators of this approach are not robust against phenotypic outliers. As a result, it fails to detect true QTL positions in presence of outliers. In this study, we investigated the performance of β-Composite Interval Mapping (BetaCIM) for detecting both linked and unlinked important QTLs positions from the robustness points of views. Performance of this approach depends on the value of tuning parameter β. It reduces to the classical CIM approach for β →0. We described and formulated the cross-validation procedure for selecting trait specific optimum value of β. It was observed that the optimum value of β depends on both amount of contaminated observations and their scatteredness. BetaCIM approach discover similar QTL positions as classical IM/CIM in absence of phenotypic outliers, but gives better results in presence of phenotypic outliers in terms of detecting true QTLs and effects estimation. We formulated the generalized forms of robust QTL analysis and developed an R-package named “BetaCIM” by implementing this robust approach. Left and right kidney weight data sets of mouse intercross population (129 S1/SvlmJ × A/J) were analyzed by using BetaCIM, CIM, and IM approaches. For right kidney weight (RKW) CIM and BetaCIM provided similar LOD score profile, and both approaches identified 3 QTL positions. IM approach also identified 3 QTL positions. For left kidney weight (LKW), there was evidence of one outlying observation; and in this case the BetaCIM approach identified 2 QTL positions. However, none of the QTLs were significant by CIM and IM approaches at 5% level of significance. Gene expression ontology (GEO) search showed that the candidate genes (Otof and A330033J07Rik) of the identified QTLs for LKW were expressed in kidney. Both simulation and real data analysis results showed that BetaCIM approach improves the performance over the existing methods in presence of phenotypic outliers. Otherwise, it keeps almost equal performance.