Over the past ten years, more than 4,000 genome-wide association studies (GWAS) have helped to shed light on the genetic architecture of complex traits and diseases. In recent years, phenotyping of the samples has often gone beyond single traits and it has become common to record multi- to high-dimensional phenotypes for individu- als. Whilst these rich datasets offer the potential to analyse complex trait structures and pleiotropic effects at a genome-wide level, novel analytic challenges arise. This thesis summarises my research into genetic associations for high-dimensional phen- otype data. First, I developed a novel and computationally efficient approach for multivari- ate analysis of high-dimensional phenotypes based on linear mixed models, com- bined with bootstrapping (LiMMBo). Both in simulation studies and on real data, I demonstrate the statistical validity of LiMMBo and that it can scale to hundreds of phenotypes. I show the gain in power of multivariate analyses for high-dimensional phenotypes compared to univariate approaches, and illustrate that LiMMBo allows for detecting pleiotropy in a large number of phenotypic traits. Aside from their computational challenges in GWAS, the true dimensionality of very high-dimensional phenotypes is often unknown and lies hidden in high-dimen- sional space. Retaining maximum power for association studies of such phenotype data relies on using an appropriate phenotype representation. I systematically ana- lysed twelve unsupervised dimensionality reduction methods based on their per- formance in finding a robust phenotype representation in simulated data of different structure and size. I propose a stability criteria for choosing low-dimensional phen- otype representations and demonstrate that stable phenotypes can recover genetic associations. Finally, I analysed genetic variants for associations to high-dimensional cardiac phenotypes based on MRI data from 1,500 healthy individuals. I used an unsuper- vised approach to extract a low-dimensional representation of cardiac wall thickness and conducted a GWAS on this representation. In addition, I investigated genetic associations to a trabeculation phenotype generated from a supervised feature ex- traction approach on the cardiac MRI data. In summary, this thesis highlights and overcomes some of the challenges in per- forming genetic association studies on high-dimensional phenotypes. It describes new approaches for phenotype processing, and genotype to phenotype mapping for high-dimensional datasets, as well as providing new insights in the genetic structure of cardiac morphology in humans.

SLMAP is a tail anchored membrane protein that alternatively splices to generate three isoforms, SLMAP1, SLMAP2 and SLMAP3. Previous studies in our lab have shown that the postnatal cardiac-specific overexpression of SLMAP1 results in intracellular vesicle expansion and enhanced endosomal recycling. I generated a postnatal cardiac-specific knockout model using the Cre-Lox system to nullify all three SLMAP isoforms and further evaluate its role in the mouse myocardium. SLMAP knockdown and knockout mouse hearts were analyzed with western blotting and qPCR. I found that only SLMAP3 was nullified and phenotypic evaluation through echocardiography indicated that young and old SLMAP3 knockout animals showed no remarkable changes in cardiac function. Furthermore, challenge with stressor isoproterenol had a similar response to wildtype and knockout mice in cardiac structure and function. Surprisingly the level of expression of SLMAP1 and SLMAP2 was maintained in the myocardium from SLMAP3 deficient mice. Interestingly the machinery involved in endosomal recycling was not impacted by the loss of SLMAP3. These data indicate that loss of SLMAP3 does not alter cardiac structure and function in the postnatal myocardium in the presence of SLMAP1 and SLMAP2.