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Frånberg, M. (2019). Statistical methods for detecting gene-gene and gene-environment interactions in genome-wide association studies. (Doctoral dissertation). Stockholm: KTH Royal Institute of Technology
Öppna denna publikation i ny flik eller fönster >>Statistical methods for detecting gene-gene and gene-environment interactions in genome-wide association studies
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH Royal Institute of Technology, 2019. s. 56
TRITA-EECS-AVL ; 2019:46
Nationell ämneskategori
Datavetenskap (datalogi)
urn:nbn:se:kth:diva-250730 (URN)978-91-7873-189-3 (ISBN)
2019-05-28, Fire, Science for Life Laboratory, Tomtebodavägen 23A, Solna, 10:00 (Engelska)

QC 20190507

Tillgänglig från: 2019-05-07 Skapad: 2019-05-03 Senast uppdaterad: 2019-05-07Bibliografiskt granskad
Frånberg, M., Strawbridge, R. J., Hamsten, A., de Faire, U., Lagergren, J. & Sennblad, B. (2017). Fast and general tests of genetic interaction for genome-wide association studies. PloS Computational Biology, 13(6), Article ID e1005556.
Öppna denna publikation i ny flik eller fönster >>Fast and general tests of genetic interaction for genome-wide association studies
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2017 (Engelska)Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, nr 6, artikel-id e1005556Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Nationell ämneskategori
Biologiska vetenskaper
urn:nbn:se:kth:diva-211406 (URN)10.1371/journal.pcbi.1005556 (DOI)000404565400019 ()2-s2.0-85021747478 (Scopus ID)

QC 20170804

Tillgänglig från: 2017-08-04 Skapad: 2017-08-04 Senast uppdaterad: 2019-05-07Bibliografiskt granskad
Frånberg, M., Gertow, K., Hamsten, A., Lagergren, J. & Sennblad, B. (2015). Discovering Genetic Interactions in Large-Scale Association Studies by Stage-wise Likelihood Ratio Tests. PLoS Genetics, 11(9), Article ID e1005502.
Öppna denna publikation i ny flik eller fönster >>Discovering Genetic Interactions in Large-Scale Association Studies by Stage-wise Likelihood Ratio Tests
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2015 (Engelska)Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 9, artikel-id e1005502Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Despite the success of genome-wide association studies in medical genetics, the underlying genetics of many complex diseases remains enigmatic. One plausible reason for this could be the failure to account for the presence of genetic interactions in current analyses. Exhaustive investigations of interactions are typically infeasible because the vast number of possible interactions impose hard statistical and computational challenges. There is, therefore, a need for computationally efficient methods that build on models appropriately capturing interaction. We introduce a new methodology where we augment the interaction hypothesis with a set of simpler hypotheses that are tested, in order of their complexity, against a saturated alternative hypothesis representing interaction. This sequential testing provides an efficient way to reduce the number of non-interacting variant pairs before the final interaction test. We devise two different methods, one that relies on a priori estimated numbers of marginally associated variants to correct for multiple tests, and a second that does this adaptively. We show that our methodology in general has an improved statistical power in comparison to seven other methods, and, using the idea of closed testing, that it controls the family-wise error rate. We apply our methodology to genetic data from the PRO-CARDIS coronary artery disease case/control cohort and discover three distinct interactions. While analyses on simulated data suggest that the statistical power may suffice for an exhaustive search of all variant pairs in ideal cases, we explore strategies for a priori selecting subsets of variant pairs to test. Our new methodology facilitates identification of new disease-relevant interactions from existing and future genome-wide association data, which may involve genes with previously unknown association to the disease. Moreover, it enables construction of interaction networks that provide a systems biology view of complex diseases, serving as a basis for more comprehensive understanding of disease pathophysiology and its clinical consequences.

Nationell ämneskategori
Biologiska vetenskaper
urn:nbn:se:kth:diva-175933 (URN)10.1371/journal.pgen.1005502 (DOI)000362269000023 ()26402789 (PubMedID)2-s2.0-84943520457 (Scopus ID)
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish e‐Science Research CenterHjärt-Lungfonden, 20140433Magnus Bergvalls StiftelseStiftelsen Gamla Tjänarinnor, 2014-00090Vetenskapsrådet, 2013-4993

QC 20151103

Tillgänglig från: 2015-11-03 Skapad: 2015-10-26 Senast uppdaterad: 2019-05-07Bibliografiskt granskad
ORCID-id: ORCID iD iconorcid.org/0000-0002-0749-9903

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