MBD-seq as a cost-effective approach for methylome-wide association studies: demonstration in 1500 case–control samples

Author:

Aberg Karolina A1,McClay Joseph L1,Nerella Srilaxmi1,Xie Lin Y1,Clark Shaunna L1,Hudson Alexandra D1,Bukszár Jozsef1,Adkins Daniel1,Consortium Swedish Schizophrenia,Hultman Christina M2,Sullivan Patrick F3,Magnusson Patrik KE2,van den Oord Edwin JCG4

Affiliation:

1. Center for Biomarker Research & Personalized Medicine, School of Pharmacy, Virginia Commonwealth University, 1112 East Clay Street, PO Box 980533, Richmond, VA 23298, USA

2. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden

3. Department of Genetics, University of North Carolina School of Medicine, Genetic Medicine Building CB 7264 Chapel Hill, NC 27599, USA

4. Center for Biomarker Research & Personalized Medicine, School of Pharmacy, Virginia Commonwealth University, 1112 East Clay Street, PO Box 980533, Richmond, VA 23298, USA.

Abstract

Aim: We studied the use of methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq) as a cost-effective screening tool for methylome-wide association studies (MWAS). Materials & methods: Because MBD-seq has not yet been applied on a large scale, we first developed and tested a pipeline for data processing using 1500 schizophrenia cases and controls plus 75 technical replicates with an average of 68 million reads per sample. This involved the use of technical replicates to optimize quality control for multi- and duplicate-reads, an in silico experiment to identify CpGs in loci with alignment problems, CpG coverage calculations based on multiparametric estimates of the fragment size distribution, a two-stage adaptive algorithm to combine data from correlated adjacent CpG sites, principal component analyses to control for confounders and new software tailored to handle the large data set. Results: We replicated MWAS findings in independent samples using a different technology that provided single base resolution. In an MWAS of age-related methylation changes, one of our top findings was a previously reported robust association involving GRIA2. Our results also suggested that owing to the many confounding effects, a considerable challenge in MWAS is to identify those effects that are informative about disease processes. Conclusion: This study showed the potential of MBD-seq as a cost-effective tool in large-scale disease studies.

Publisher

Future Medicine Ltd

Subject

Cancer Research,Genetics

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