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Leveraging genetic association data to investigate the polygenic architecture of human traits and diseases The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Chan, Ying Leong. 2014. Leveraging genetic association data to Citation investigate the polygenic architecture of human traits and diseases. Doctoral dissertation, Harvard University. Accessed April 17, 2018 4:56:35 PM EDT Citable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274191 This article was downloaded from Harvard University's DASH Terms of Use repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA (Article begins on next page) Leveraging genetic association data to investigate the polygenic architecture of human traits and diseases A dissertation presented by Ying Leong Chan to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Genetics and Genomics Harvard University Cambridge, Massachusetts April 2014 © 2014 Ying Leong Chan All rights reserved. Dissertation Advisor: Professor Joel N. Hirschhorn Ying Leong Chan Leveraging genetic association data to investigate the polygenic architecture of human traits and diseases ABSTRACT Many human traits and diseases have a polygenic architecture, where phenotype is partially determined by variation in many genes. These complex traits or diseases can be highly heritable and genome-wide association studies (GWAS) have been relatively successful in the identification of associated variants. However, these variants typically do not account for most of the heritability and thus, the genetic architecture remains uncertain. This dissertation describes analytical approaches to look for evidence of models of genetic architecture that could explain the remaining heritability. We develop methods to make predictions under various models, and compare the expected results from these predictions against the observed data for several traits and diseases. First, in studies of height (a classical polygenic trait), we modeled the expected cumulative effect of common variants identified from GWAS and compared the model with empirical data in individuals from the tails of the height distribution. We found that these common variants are predictive of stature, but have less than expected effects specifically at the short end of the height distribution. This result is consistent with models where rare variants with moderate effect, influence stature only in the shortest individuals. Second, we showed that under genetic models where low frequency variants make iii polygenic contributions to disease, there will be an excess of low frequency risk-increasing variants detected in GWAS. As such, by comparing the number of detected risk-increasing to risk-decreasing variants, one can detect a signal of the contribution to polygenic inheritance from low frequency variants. Finally, we examine the genetic architecture of sitting height ratio (SHR), a measure of body proportion that varies dramatically between individuals of African and European ancestry. We find that the SHR difference between populations is largely due to polygenic architecture; there is no evidence for any major locus accounting for most of this difference. These results show that, with the appropriate computational and genetic models, one can use empirical results of genetics studies to make inferences regarding genetic architecture of human traits and diseases. Doing so can help investigators prioritize strategies for uncovering the remaining unexplained heritability. iv TABLE OF CONTENTS Abstract iii Dedication vi Acknowledgements vii Attributions xi Chapter 1: Introduction 1 A Preamble 2 Heritability of complex traits 7 Methods for studying the genetics of complex traits 12 Complex phenotypes 21 Heritability of human traits 18 Accumulating evidence from multiple studies 25 Summary 29 Chapter 2: Common variants show predicted polygenic effects on height in the tails of 38 the distribution, except in extremely short individuals Chapter 3: An excess of risk-increasing low frequency variants can be a signal of 85 polygenic inheritance in complex diseases Chapter 4: Genome wide association in European and African Americans discover novel 136 loci associated with sitting height ratio Chapter 5: Concluding remarks 169 Overview 170 Major findings and implications 170 Future Directions 174 A Postscript 178 v DEDICATION I dedicate this thesis to my loving wife, Teng Ting (Elaine) Lim. You are the person that has always been there during difficult and trying times. We share and do almost everything together. I would not be the person I am today without your love and support. Elaine, I dedicate this thesis to you. vi ACKNOWLEGEMENTS When I first arrived on the Harvard Medical School campus, I was captivated by the breath and majesty of just being there. Besides the Victorian building design of the Quad buildings, the place was surrounded by many hospitals and people plus that the sound of sirens wailing from ambulances made the whole area a really busy place. It was recruitment weekend for new students and part of the program was to have a couple of faculty members give talks to the potential incoming students and there was where I met my eventual dissertation advisor, Joel Hirschhorn. It was March of 2009. I rotated in the Hirschhorn lab for the summer of that year and eventually joined the lab as a student the next year. Joel was extremely helpful and encouraging mentor throughout graduate school. We (members of the lab) meet regularly with him, at least once in two weeks (30 to 60 minutes) despite his extremely busy schedule and we will always get his full undivided attention during each session. Also, during lab meetings, he will always be there to give critical feedback and suggestions when you present your work and ideas, whether it is about possible experiments to perform or just feedback on giving the presentation itself. Furthermore, he sometimes performs his own analysis, contrary to the long held belief that “PIs don’t do experiments themselves”. To me, it is a privilege to have the opportunity to be his student as well as a member of his lab. I remember when I first joined the lab, I was given the task of “coming up with 10 ideas” by Joel. I only did 8 and after long discussions about each of the aims, 1 of them eventually became one of my thesis aims with the help of another member of the lab, Andrew Dauber. My time in graduate school would not be the same without Andrew. Andrew started as a fellow in the lab the same time when I started my rotation so he has been in the lab for about a year when I vii eventually joined. It was during one of the lab meetings that Andrew presented some genotyping data on height extremes (very short and tall individuals) that could answer one of the 8 ideas that I had initially. Andrew was very kind and helpful and we worked together to answer the question. I will always be grateful to Andrew for getting me started as well as his mentorship throughout my time in the lab. Rany Salem, a post doctoral fellow in the lab, is someone I would also like to specially mention. Rany started as a post doctoral fellow the same day I started my rotation in the lab. Although, he is based at the Broad Institute, he comes to Children’s (Boston Children’s Hospital) frequently and we would always get coffee and exchange ideas. His work on diabetic nephropathy allowed me to develop my next idea, using the summary statistics generated from that project. Besides that, his efforts to obtain genotype data from many different cohorts allowed me and others to explore other ideas with regards to complex traits. In general, members of the Hirschhorn lab are a very sociable bunch which is odd, considering that most of us are ‘computational’ people that do not have a reputation for being sociable. To illustrate this, a former student of the lab, who is now a post doctoral fellow, Charleston Chiang, frequently organizes “games-night” at his place (about once a month) where he invites fellow members of the lab to hang out and play board games. One of our favorite games is called “Betrayal”, which is a game about a group of adventurers exploring a haunted house and one of the members will become the “traitor” midway in the game. That was fun and I will always remember those good times. Another example worth mentioning is our regular sashimi buffets. Somehow, there is a sizeable number of people in our lab that just love gorging on raw-fish, me included. We started out at a reasonably priced restaurant called Yamato somewhere in Allston where they have an all-you-can-eat buffet for just thirty dollars. However, viii when Tonu Esko joined us midway during my time in the lab, he “discovered” a new place, called Takusan where it is cheaper and serves oysters as well. Takusan is now our regular hangout until we find a new place. Therefore, I would like to take the opportunity to thank other members of the lab, past and present for creating the wonderful lab environment that is conducive for sharing ideas and establishing collaboration. Thanks to Tune Pers for providing opportunity to work together on DEPICT. Thanks to Sophie Wang for the help in performing the forward simulations for our 2nd project as well as for free ice-cream. Thanks to Sailaja Vedamtam for pointing me to necessary files when I need them as well as for the wonderful vegetarian dinner that you make. Thanks to Tonu Esko for having the opportunity to work with the Estonian data as well as introducing Takusan Sushi.

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