A protein domain and family based approach to rare variant association analysis

Thomas Richardson, Hashem Shihab, Manuel A Rivas, Mark I McCarthy, Colin Campbell, Nicholas Timpson, Tom Gaunt

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)
319 Downloads (Pure)


Background: It has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit. 
Methods: Using Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1%) together in three different ways 1) variants within single genomic regions which map to individual protein domains 2) variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3) all variants within combined regions from multiple genes responsible for coding the same protein domain (i.e. protein families). A conventional collapsing analysis using gene coordinates was also undertaken for comparison. We used UK10K sequence data and investigated associations between regions of variants and lipid traits using the sequence kernel association test (SKAT). 
Results: We observed no strong evidence of association between regions of variants based on Pfam domain definitions and lipid traits. Quantile-Quantile plots illustrated that the overall distributions of p-values from the protein domain analyses were comparable to that of a conventional gene-based approach. Deviations from this distribution suggested that collapsing by either protein domain or gene definitions may be favourable depending on the trait analysed. 
Conclusion: We have collapsed rare variants together using protein domain and family coordinates to present an alternative approach over collapsing across conventionally used gene-based regions. Although no strong evidence of association was detected in these analyses, future studies may find still value in adopting these approaches to detect previously unidentified association signals.
Original languageEnglish
Article numbere0153803
Number of pages12
JournalPLoS ONE
Issue number4
Publication statusPublished - 29 Apr 2016


  • Rare Variant Analysis
  • Protein Domains
  • Functional annotations
  • UK10K
  • Whole Genome Sequencing


Dive into the research topics of 'A protein domain and family based approach to rare variant association analysis'. Together they form a unique fingerprint.

Cite this