A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles
Jenna C. Carlson,
Mohanraj Krishnan,
Samantha L. Rosenthal,
Emily M. Russell,
Jerry Z. Zhang,
Nicola L. Hawley,
Jaye Moors,
Hong Cheng,
Nicola Dalbeth,
Janak R. de Zoysa,
Huti Watson,
Muhammad Qasim,
Rinki Murphy,
Take Naseri,
Muagututi’a Sefuiva Reupena,
Satupa‘itea Viali,
Lisa K. Stamp,
John Tuitele,
Erin E. Kershaw,
Ranjan Deka,
Stephen T. McGarvey,
Tony R. Merriman,
Daniel E. Weeks,
Ryan L. Minster
Affiliations
Jenna C. Carlson
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding author
Mohanraj Krishnan
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
Samantha L. Rosenthal
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, USA
Emily M. Russell
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
Jerry Z. Zhang
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
Nicola L. Hawley
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
Jaye Moors
Department of Biochemistry, University of Otago, Dunedin, New Zealand
Hong Cheng
Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
Nicola Dalbeth
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
Janak R. de Zoysa
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
Huti Watson
Ngāti Porou Hauora Charitable Trust, Te Puia Springs, Tairāwhiti East Coast, New Zealand
Muhammad Qasim
Ngāti Porou Hauora Charitable Trust, Te Puia Springs, Tairāwhiti East Coast, New Zealand
Rinki Murphy
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
Take Naseri
Ministry of Health, Government of Samoa, Apia, Samoa
Muagututi’a Sefuiva Reupena
Lutia i Puava ae Mapu i Fagalele, Apia, Samoa
Satupa‘itea Viali
School of Medicine, National University of Samoa, Apia, Samoa
Lisa K. Stamp
Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
John Tuitele
Department of Public Health, Government of American Samoa, Pago Pago, American Samoa
Erin E. Kershaw
Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Ranjan Deka
Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
Stephen T. McGarvey
International Health Institute, Department of Epidemiology, Brown University, Providence, RI, USA; Department of Anthropology, Brown University, Providence, RI, USA
Tony R. Merriman
Department of Biochemistry, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
Daniel E. Weeks
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
Ryan L. Minster
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
Summary: Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here, we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218∗; posterior probability = 0.9987) in BTNL9 and both lower HDL-C and greater triglycerides (TGs). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association (βHDL-C = −1.60 mg/dL, pHDL-C = 7.63 × 10−10; βTG = 12.00 mg/dL, pTG = 3.82 × 10−7). While this variant appears to be Polynesian specific, there is also evidence of association from other multiancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.
