Integrated Genome-Wide Pathway Association Analysis with INTERSNP

Herold, Christine; Mattheisen, Manuel; Lacour, André; Vaitsiakhovich, Tatsiana; Angisch, Marina; Drichel, Dmitriy; Becker, Tim

doi:10.1159/000336196

Cited by 11 publications

(8 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our GDM approach is complementary in this case, as it allows for relative allelic responses to be simultaneously characterized across predictor variables. Approaches that characterize gene interactions may further elucidate the polygenic basis of environmental adaptation (e.g., Herold et al, 2012;Lee & Mitchell-Olds, 2012 Chauhan et al (2014Chauhan et al ( , 2016 (visual processing and thermal stress), while we found additional support for strong selection on genes involved in ion transport (V-ATPase) and other cellular processes.…”

Section: Broad Allelic Frequency Changes Across the Range Expansionmentioning

confidence: 63%

See 1 more Smart Citation

Signatures of local adaptation along environmental gradients in a range‐expanding damselfly (Ischnura elegans)

et al. 2018

View full text Add to dashboard Cite

Insect distributions are shifting rapidly in response to climate change and are undergoing rapid evolutionary change. We investigate the molecular signatures underlying local adaptation in the range-expanding damselfly, Ischnura elegans. Using a landscape genomic approach combined with generalized dissimilarity modelling (GDM), we detect selection signatures on loci via allelic frequency change along environmental gradients. We analyse 13,612 single nucleotide polymorphisms (SNPs), derived from restriction site-associated DNA sequencing (RADseq), in 426 individuals from 25 sites spanning the I. elegans distribution in Sweden, including its expanding northern range edge. Environmental association analysis (EAA) and the magnitude of allele frequency change along the range expansion gradient revealed significant signatures of selection in relation to high maximum summer temperature, high mean annual precipitation and low wind speeds at the range edge. SNP annotations with significant signatures of selection revealed gene functions associated with ongoing range expansion, including heat shock proteins (HSP40 and HSP70), ion transport (V-ATPase) and visual processes (long-wavelength-sensitive opsin), which have implications for thermal stress response, salinity tolerance and mate discrimination, respectively. We also identified environmental thresholds where climate-mediated selection is likely to be strong, and indicate that I. elegans is rapidly adapting to the climatic environment during its ongoing range expansion. Our findings empirically validate an integrative approach for detecting spatially explicit signatures of local adaptation along environmental gradients.

show abstract

Section: Broad Allelic Frequency Changes Across the Range Expansionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Signatures of local adaptation along environmental gradients in a range‐expanding damselfly (Ischnura elegans)

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Multi-SNP approaches like interaction and pathway analysis were proposed [3] to detect the still unexplained portion of genetic disease risk. While Genome-wide interaction analysis has become computationally feasible [4], [5], by now only few, if any, replicable interactions have been found. In order to explain the phenomenon of missing evidence for interaction, Zuk et al [6] suggested that common diseases may follow so-called limiting pathway liability models (LPLMs).…”

Section: Introductionmentioning

confidence: 99%

A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects

et al. 2013

Self Cite

View full text Add to dashboard Cite

Deviation from multiplicativity of genetic risk factors is biologically plausible and might explain why Genome-wide association studies (GWAS) so far could unravel only a portion of disease heritability. Still, evidence for SNP-SNP epistasis has rarely been reported, suggesting that 2-SNP models are overly simplistic. In this context, it was recently proposed that the genetic architecture of complex diseases could follow limiting pathway models. These models are defined by a critical risk allele load and imply multiple high-dimensional interactions. Here, we present a computationally efficient one-degree-of-freedom “supra-multiplicativity-test” (SMT) for SNP sets of size 2 to 500 that is designed to detect risk alleles whose joint effect is fortified when they occur together in the same individual. Via a simulation study we show that the SMT is powerful in the presence of threshold models, even when only about 30–45% of the model SNPs are available. In addition, we demonstrate that the SMT outperforms standard interaction analysis under recessive models involving just a few SNPs. We apply our test to 10 consensus Alzheimer’s disease (AD) susceptibility SNPs that were previously identified by GWAS and obtain evidence for supra-multiplicativity () that is not attributable to either two-way or three-way interaction.

show abstract

“…are another issue that we will explore in greater depth using the example of INTERSNP (14,18), a popular software tool used for GWAS of case-control SNP data and quantitative traits. The algorithm behind INTERSNP belongs to the class of linear Euclidean measures and models relationships between genomic variables such as Y, X and non-genomic variables U as a linear regression (when variables U are assumed to be explicitly available as data -i.e.…”

Section: Errors Introduced By the Underlying Modelmentioning

confidence: 99%

Imputation of posterior linkage probability relations reveals a significant influence of structural 3D constraints on linkage disequilibrium

Gerber

Fournier

Hewel

et al. 2018

Preprint

View full text Add to dashboard Cite

Genetic association studies have become increasingly important in unraveling the genetics of diseases or complex traits. Despite their value for modern genetics, conflicting conclusions often arise through the difficulty of confirming and replicating experimental results. We argue that this problem is largely based on the application of statistical relation measures that are not appropriate for genomic data analysis and demonstrate that the standard measures used for Genome-wide association studies or genomics linkage analysis bear a statistic bias. This may come from the violation of underlying assumptions (such as independence or stationarity) as well as from other conceptual limitations in the measures or relations, such as missing invariance with respect to coding or the inability to reflect latent factors. Attempts to introduce unbiased relation measures that avoid these limitations are usually computationally expensive and do not scale for large data sizes being typical for genomics applications.To tackle these problems, we propose a straightforwardly computable relation measure called Linkage Probability (LP). This measure provides the posterior probability of a relation between two categorical data sets and considers potential biases from latent variables. We compare several aspects of popular relation measures through an illustrative example and human genomics data. We demonstrate that the application of LP to the analysis of Single Nucleotide Polymorphisms (SNP) reveals latent 3D steric effects within 1D SNP data, that approximate to chromatin loops captured by high resolution Hi-C maps. Relation measure| Genome Wide Association Studies| Multiscale processes| Information criteria| Numerical methods

show abstract

Integrated Genome-Wide Pathway Association Analysis with INTERSNP

Cited by 11 publications

References 55 publications

Signatures of local adaptation along environmental gradients in a range‐expanding damselfly (Ischnura elegans)

Signatures of local adaptation along environmental gradients in a range‐expanding damselfly (Ischnura elegans)

A One-Degree-of-Freedom Test for Supra-Multiplicativity of SNP Effects

Imputation of posterior linkage probability relations reveals a significant influence of structural 3D constraints on linkage disequilibrium

Contact Info

Product

Resources

About