Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis

M Taipale; E Jakkula; O-P Kämäräinen; P Gao; S Skarp; S Barral; I Kiviranta; H Kröger; J Ott; G-H Wei; L Ala-Kokko; M Männikkö

doi:10.1016/j.joca.2015.10.019

Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis

Osteoarthritis Cartilage. 2016 Apr;24(4):655-63. doi: 10.1016/j.joca.2015.10.019. Epub 2015 Nov 19.

Authors

M Taipale¹, E Jakkula², O-P Kämäräinen³, P Gao³, S Skarp¹, S Barral⁴, I Kiviranta⁵, H Kröger⁶, J Ott⁷, G-H Wei³, L Ala-Kokko⁸, M Männikkö⁹

Affiliations

¹ Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Center for Life Course Epidemiology and Systems Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
² Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
³ Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland.
⁴ Gertrude H. Sergievsky Center, College for Physicians and Surgeons, Columbia University, New York, USA.
⁵ Department of Orthopaedics and Traumatology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Department of Orthopaedics and Traumatology, Jyväskylä Central Hospital, Jyväskylä, Finland.
⁶ Department of Orthopaedics and Traumatology, Kuopio University Hospital, Kuopio, Finland; Bone and Cartilage Research Unit, University of Eastern Finland, Kuopio, Finland.
⁷ Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
⁸ Connective Tissue Gene Tests, Allentown, PA, USA.
⁹ Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Center for Life Course Epidemiology and Systems Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland. Electronic address: minna.mannikko@oulu.fi.

PMID: 26603474
DOI: 10.1016/j.joca.2015.10.019

Abstract

Objective: The aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families.

Methods: Genome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family.

Results: Genome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele.

Conclusion: A potentially novel functional OA susceptibility variant was identified by targeted re-sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis.

Keywords: Enhancer element; Hip; Knee; Linkage analysis; Next generation sequencing; Osteoarthritis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromosomes, Human, Pair 2 / genetics*
Exome / genetics
Female
Genetic Linkage*
Genetic Predisposition to Disease
Genome-Wide Association Study
High-Throughput Nucleotide Sequencing / methods
Humans
Lod Score
Male
Middle Aged
Osteoarthritis, Hip / genetics*
Osteoarthritis, Knee / genetics*
Pedigree