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Fast and general tests of genetic interaction for genome-wide association studies
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2017 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, no 6, article id e1005556Article in journal (Refereed) Published
Abstract [en]

A complex disease has, by definition, multiple genetic causes. In theory, these causes could be identified individually, but their identification will likely benefit from informed use of anticipated interactions between causes. In addition, characterizing and understanding interactions must be considered key to revealing the etiology of any complex disease. Large-scale collaborative efforts are now paving the way for comprehensive studies of interaction. As a consequence, there is a need for methods with a computational efficiency sufficient for modern data sets as well as for improvements of statistical accuracy and power. Another issue is that, currently, the relation between different methods for interaction inference is in many cases not transparent, complicating the comparison and interpretation of results between different interaction studies. In this paper we present computationally efficient tests of interaction for the complete family of generalized linear models (GLMs). The tests can be applied for inference of single or multiple interaction parameters, but we show, by simulation, that jointly testing the full set of interaction parameters yields superior power and control of false positive rate. Based on these tests we also describe how to combine results from multiple independent studies of interaction in a meta-analysis. We investigate the impact of several assumptions commonly made when modeling interactions. We also show that, across the important class of models with a full set of interaction parameters, jointly testing the interaction parameters yields identical results. Further, we apply our method to genetic data for cardiovascular disease. This allowed us to identify a putative interaction involved in Lp(a) plasma levels between two 'tag' variants in the LPA locus (p = 2.42 . 10(-09)) as well as replicate the interaction (p = 6.97 . 10(-07)). Finally, our meta-analysis method is used in a small (N = 16,181) study of interactions in myocardial infarction.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2017. Vol. 13, no 6, article id e1005556
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-211406DOI: 10.1371/journal.pcbi.1005556ISI: 000404565400019Scopus ID: 2-s2.0-85021747478OAI: oai:DiVA.org:kth-211406DiVA, id: diva2:1129567
Note

QC 20170804

Available from: 2017-08-04 Created: 2017-08-04 Last updated: 2019-05-07Bibliographically approved
In thesis
1. Statistical methods for detecting gene-gene and gene-environment interactions in genome-wide association studies
Open this publication in new window or tab >>Statistical methods for detecting gene-gene and gene-environment interactions in genome-wide association studies
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite considerable effort to elucidate the genetic architecture of multi-factorial traits and diseases, there remains a gap between the estimated heritability (e.g., from twin studies) and the heritability explained by discovered genetic variants. The existence of interactions between different genes, and between genes and the environment, has frequently been hypothesized as a likely cause of this discrepancy. However, the statistical inference of interactions is plagued by limited sample sizes, high computational requirements, and incomplete knowledge of how the measurement scale and parameterization affect the analysis.

This thesis addresses the major statistical, computational, and modeling issues that hamper large-scale interaction studies today. Furthermore, it investigates whether gene-gene and gene-environment interactions are significantly involved in the development of diseases linked to atherosclerosis. Firstly, I develop two statistical methods that can be used to study of gene-gene interactions: the first is tailored for limited sample size situations, and the second enables multiple analyses to be combined into large meta-analyses. I perform comprehensive simulation studies to determine that these methods have higher or equal statistical power than contemporary methods, scale-invariance is required to guard against false positives, and that saturated parameterizations perform well in terms of statistical power. In two studies, I apply the two proposed methods to case/control data from myocardial infarction and associated phenotypes. In both studies, we identify putative interactions for myocardial infarction but are unable to replicate the interactions in a separate cohort. In the second study, however, we identify and replicate a putative interaction involved in Lp(a) plasma levels between two variants rs3103353 and rs9458157. Secondly, I develop a multivariate statistical method that simultaneously estimates the effects of genetic variants, environmental variables, and their interactions. I show by extensive simulations that this method achieves statistical power close to the optimal oracle method. We use this method to study the involvement of gene-environment interactions in intima-media thickness, a phenotype relevant for coronary artery disease. We identify a putative interaction between a genetic variant in the KCTD8 gene and alcohol use, thus suggesting an influence on intima-media thickness. The methods developed to support the analyses in this thesis as well as a selection of other prominent methods in the field is implemented in a software package called besiq.

In conclusion, this thesis presents statistical methods, and the associated software, that allows large-scale studies of gene-gene and gene-environment interactions to be effortlessly undertaken.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019. p. 56
Series
TRITA-EECS-AVL ; 2019:46
National Category
Computer Sciences
Research subject
Computer Science
Identifiers
urn:nbn:se:kth:diva-250730 (URN)978-91-7873-189-3 (ISBN)
Public defence
2019-05-28, Fire, Science for Life Laboratory, Tomtebodavägen 23A, Solna, 10:00 (English)
Opponent
Supervisors
Note

QC 20190507

Available from: 2019-05-07 Created: 2019-05-03 Last updated: 2019-05-07Bibliographically approved

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Frånberg, Mattias

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