Universität zu Köln

Kanoungi, George ORCID: 0000-0002-2452-8526 and Nothnagel, Michael ORCID: 0000-0001-8305-7114 (2018). Pathway-induced allelic spectra of diseases in the presence of strong genetic effects. Hum. Genet., 137 (3). S. 215 - 231. NEW YORK: SPRINGER. ISSN 1432-1203

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Abstract

Complex diseases are frequently modeled as following an additive model that excludes both intra- and inter-locus interaction, while at the same time reports on non-additive biological structures are ample, prominently featuring numerous metabolic and signaling pathways. Using extensive forward population simulations, we explored the impact of three basic pathway motifs on the relationship between epidemiological parameters, including disease prevalence, relative risk, sibling recurrence risk as well as causal variant number and allele frequency. We found that some but not all pathway motifs can shift the relationships between these parameters in comparison to the classical additive liability threshold model. The strongest deviations were observed with linear, cascade-like motifs that form an integral part of many reported pathways. We also modeled maturity-onset diabetes of the young (MODY) as a combination of different basic pathway motifs and observed a good concordance in epidemiological parameter values between our simulated data under this model and those reported in the literature. Given the widespread nature of pathways, including those in the etiology of human diseases, our results re-emphasize the need for non-additive interaction modeling of genetic variants to become an additional standard approach in analyzing human genetic data.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kanoungi, George UNSPECIFIED orcid.org/0000-0002-2452-8526 UNSPECIFIED Nothnagel, Michael UNSPECIFIED orcid.org/0000-0001-8305-7114 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-194263
DOI:	10.1007/s00439-018-1872-5
Journal or Publication Title:	Hum. Genet.
Volume:	137
Number:	3
Page Range:	S. 215 - 231
Date:	2018
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1203
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; HUMAN TRAIT GENES; TRANSCRIPTION FACTORS; CLINICAL-DIAGNOSIS; MULTILOCUS MODELS; COMPLEX TRAITS; RELATIVE RISK; YOUNG MODY; MUTATIONS; HERITABILITY Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19426