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. 2017 Jul 24;10:25.
doi: 10.1186/s13040-017-0145-5. eCollection 2017.

Discovery and Replication of SNP-SNP Interactions for Quantitative Lipid Traits in Over 60,000 Individuals

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Free PMC article

Discovery and Replication of SNP-SNP Interactions for Quantitative Lipid Traits in Over 60,000 Individuals

Emily R Holzinger et al. BioData Min. .
Free PMC article

Abstract

Background: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).

Results: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.

Conclusions: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

Keywords: Computational genetics; Genetic epidemiology; Genetics; Interactions; Lipids.

Conflict of interest statement

Ethics approval and consent to participate

CARe cohorts in this study are ARIC, CARDIA, CHS, FHS, and MESA. The Institutional Review Boards (IRBs) of each CARe cohort (i.e., the IRBs for each cohort’s field centers, coordinating center, and laboratory center) have reviewed the cohort’s interaction with CARe. CARe itself has been approved by the Committee on the Use of Humans as Experimental Subjects (COUHES) of the Massachusetts Institute of Technology. Identifiers were removed and codes were assigned to any protected health information (PHI) transmitted to the CARe Data Repository, with a Certificate of Confidentiality issued by the National Institutes of Health. All eMERGE sites are based on DNA biobanks linked to electronic health records approved by each Institution’s IRB. Identifiers were removed and all data was shared in the eMERGE network as de-identified data.

The BOSS methods were approved by the internal review board of the University of Wisconsin, Madison, and all participants provided written informed consent.

The BWHHS is a cohort of 4286 women, born between 1919 and 1940, randomly selected from general practitioner lists in 23 British towns. Baseline data were collected between 1999 and 2001. Relevant British ethics committee approval was received for this study.

The CLEAR study was approved by both the University of Washington and the Veterans Affairs Puget Sound Health Care System human subject review processes. Subjects gave written informed consent.

The EPIC-NL cohort comprises the Monitoring Project on Risk Factors for Chronic Diseases (MORGEN) and Prospect cohorts. All participants gave written informed consent prior to study inclusion. Both cohorts comply with the Declaration of Helsinki. Prospect was approved by the Institutional Review Board of the University Medical Centre Utrecht and MORGEN was approved by the Medical Ethics Committee of the Netherlands Organization for Applied Scientific Research.

For the GIRaFH cohort, written informed consent was obtained from all living patients. The Ethics Institutional Review Board of each participating hospital approved the protocol.

For all KORA studies approval is sought from the Ethics Committee of the Bavarian Medical Association (Bayerische Landesärztekammer) and the Bavarian commissioner for data protection and privacy (Bayerischer Datenschutzbeauftragter). All study participants provide written consent after being informed about the study. All subjects have the option to restrict their consent to specific procedures, e. g. by denying storage of biosamples.

The LURIC study was approved by the institutionalreview board of the ethics committee of the Landesärztekammer Rheinland-Pfalz (No. 1997–203) and was performed in adherence to the principles of the Declaration of Helsinki. All subjects gave written informed consent.

The PROCARDIS protocol was approved by the ethics committee at each participating center, and all subjects provided written informed consent.

All Whitehall II participants gave written informed consent. Participant consent and research ethics approvals (University College London (UCL) ethics committee) were renewed at each contact; latest approved was by the Joint UCL/UCLH Committee on the Ethics of Human Research (Committee Alpha), reference number 85/0938.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flowchart of the quality control and analysis steps for the discovery and replication phases
Fig. 2
Fig. 2
Pairwise r2 values for SNPs in top models for main effect filtering (MEF) analysis of HDL-C levels. The numbers in the boxes are r2 values and darker shading indicates higher LD. The numbers below the SNPs are an indicator of location in this region. Correlation patterns indicate three sets of SNPs and two interaction signals based on replication results (Set 1 x Set 2 and Set 2 x Set 3)
Fig. 3
Fig. 3
Pairwise r2 values for SNPs in top models for the main effect filtering (MEF) replication analysis of plasma triglyceride (TG) levels. The numbers in the boxes are r2 values and darker shading indicates higher LD. The numbers below the SNPs are an indicator of location in this region. Correlation patterns indicate a single signal representing an interaction between rs180327 (or a correlated functional variant) and the other variants for the four models that include this SNP
Fig. 4
Fig. 4
Results for the main effect filter (MEF) analysis of HDL-C. Showing results for the models that passed the replication threshold of p < 3.0 × 10–5. Orig# and prox# designate models that were identified in the discovery cohort and those identified via proxy (i.e. both SNPs in high LD with SNPs from orig. Models), respectively. V1 and V2 are the two SNPs in the model; arrow in likelihood ratio test (LRT) row denotes direction of effect
Fig. 5
Fig. 5
Results for the main effect filter (MEF) analysis of LDL-C. Showing results for the models that passed the replication threshold of p < 3.0 × 10–5. Orig# and prox# designate models that were identified in the discovery cohort and those identified via proxy (i.e. both SNPs in high LD with SNPs from orig. Models), respectively. V1 and V2 are the two SNPs in the model; arrow in likelihood ratio test (LRT) row denotes direction of effect
Fig. 6
Fig. 6
Results for the main effect filter (MEF) analysis of TC. Showing results for the models that passed the replication threshold of p < 3.0 × 10–5. Orig# and prox# designate models that were identified in the discovery cohort and those identified via proxy (i.e. both SNPs in high LD with SNPs from orig. Models), respectively. V1 and V2 are the two SNPs in the model; arrow in likelihood ratio test (LRT) row denotes direction of effect
Fig. 7
Fig. 7
Results for the main effect filter (MEF) analysis of TG. Showing results for the models that passed the replication threshold of p < 3.0 × 10–5. Orig# and prox# designate models that were identified in the discovery cohort and those identified via proxy (i.e. both SNPs in high LD with SNPs from orig. Models), respectively. V1 and V2 are the two SNPs in the model; arrow in likelihood ratio test (LRT) row denotes direction of effect
Fig. 8
Fig. 8
Results for the Biofilter analysis of TG. Showing results for the models that passed the replication threshold of p < 3.0 × 10–5. Orig# and prox# designate models that were identified in the discovery cohort and those identified via proxy (i.e. both SNPs in high LD with SNPs from orig. Models), respectively. V1 and V2 are the two SNPs in the model; arrow in likelihood ratio test (LRT) row denotes direction of effect

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