title: A Protein Domain and Family Based Approach to Rare Variant Association Analysis.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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 still find value in adopting these approaches to detect previously unidentified association signals.
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Tom G
authors.initials: TG
authors.lastname: Richardson
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Hashem A
authors.initials: HA
authors.lastname: Shihab
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Rivas
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Intelligent Systems Laboratory, University of Bristol, Bristol, United Kingdom.
authors.forename: Colin
authors.initials: C
authors.lastname: Campbell
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
mesh_terms: D015331:Cohort Studies; D003198:Computer Simulation; D004247:DNA / Q000235:genetics; D003627:Data Interpretation, Statistical; D005260:Female; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000072417:Protein Domains / Q000235:genetics*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D012042:Registries; D014427:Twins / Q000235:genetics
chemical_list: D004247:DNA