title: Diversity in non-repetitive human sequences not found in the reference genome.
abstract: Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR) sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are ancestral. Furthermore, 149 variant loci are in linkage disequilibrium (r2> 0.8) with a genome-wide association study (GWAS) catalog marker, suggesting disease relevance. Additionally, we report an association (P = 3.8 × 10-8, odds ratio (OR) = 0.92) with myocardial infarction (23,360 cases, 300,771 controls) for a 766-bp NRNR sequence variant. Our results underline the importance of including variation of all complexity levels when searching for variants that associate with disease.
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Berlin Institute of Health, Berlin, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Kehr
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Anna
authors.initials: A
authors.lastname: Helgadottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Pall
authors.initials: P
authors.lastname: Melsted
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Hakon
authors.identifier: http://orcid.org/0000-0001-6197-494X
authors.initials: H
authors.lastname: Jonsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Helgason
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Adalbjörg
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Gylfason
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Gisli H
authors.initials: GH
authors.lastname: Halldorsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Snaedis
authors.initials: S
authors.lastname: Kristmundsdottir
authors.affiliation: Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Internal Medicine, Landspitali-National University Hospital, Reykjavik, Iceland.
authors.forename: Gudmundur
authors.identifier: http://orcid.org/0000-0002-7146-1395
authors.initials: G
authors.lastname: Thorgeirsson
authors.affiliation: Department of Clinical Biochemistry, Landspitali-National University Hospital, Reykjavik, Iceland.
authors.forename: Isleifur
authors.initials: I
authors.lastname: Olafsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Department of Internal Medicine, Landspitali-National University Hospital, Reykjavik, Iceland.
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0001-7123-6123
authors.initials: P
authors.lastname: Sulem
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Department of Anthropology, University of Iceland, Reykjavik, Iceland.
authors.forename: Agnar
authors.initials: A
authors.lastname: Helgason
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Science and Engineering, Reykjavik University, Reykjavik, Iceland.
authors.forename: Bjarni V
authors.identifier: http://orcid.org/0000-0003-0756-0767
authors.initials: BV
authors.lastname: Halldorsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000818:Animals; D001483:Base Sequence / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D009203:Myocardial Infarction / Q000235:genetics; D019974:Pan paniscus / Q000235:genetics; D010641:Phenotype