ARTICLE A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles Jenna C. Carlson, 1,2,18,19, * Mohanraj Krishnan, 2 Samantha L. Rosenthal, 2,3 Emily M. Russell, 2 Jerry Z. Zhang, 1 Nicola L. Hawley, 4 Jaye Moors, 5 Hong Cheng, 6 Nicola Dalbeth, 7 Janak R. de Zoysa, 7 Huti Watson, 8 Muhammad Qasim, 8 Rinki Murphy, 7,9 Take Naseri, 10 Muagututi’a Sefuiva Reupena, 11 Satupa‘itea Viali, 12 Lisa K. Stamp, 13 John Tuitele, 14 Erin E. Kershaw, 15 Ranjan Deka, 6 Stephen T. McGarvey, 16,17 Tony R. Merriman, 5,9 Daniel E. Weeks, 1,2 and Ryan L. Minster 2 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 ¼ 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 (b HDL-C ¼1.60 mg/ dL, p HDL-C ¼ 7.63 3 10 10 ; b TG ¼ 12.00 mg/dL, p TG ¼ 3.82 3 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. Introduction Atherogenic lipid profiles—increased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TGs) as well as decreased high-density lipo- protein cholesterol (HDL-C)—are well-documented and heritable risk factors for cardiovascular disease (CVD) worldwide. While behavioral modifications and medica- tion have been successful in improving lipid profiles, CVD is still the leading cause of death worldwide, particu- larly among people of Polynesian and Pacific Island ancestry. 1–5 The examination of the genetic underpinnings of lipid variation through genome-wide association studies (GWASs) has identified numerous genetic associations. These discoveries have furthered the understanding of CVD and potential therapeutic targets; however, this research has primarily come from studies in European- ancestry populations. Recent efforts to diversify research on this topic have highlighted the importance of including diverse populations for gene discovery, yielding novel asso- ciations, improved fine mapping, and better polygenic risk scores. 6 Despite this, limited effort has focused on Pol- ynesian populations, whose unique population history including genetic drift from founder effects, small popula- tion sizes, and population bottlenecks may provide insight into the biological foundations of variation in lipid levels, which would not only benefit Polynesian individuals but also those from other populations. 7–9 One region of interest is 5q35, which has previously been associated with HDL-C levels in Micronesian and Samoan populations. 10,11 The causal variant at this locus, and the biological mechanism underlying this association with an atherogenic lipid profile, is unknown. The aim of this study was to fine map this association signal in a cohort of 2,851 Samoan adults and replicate this association in several independent Polynesian cohorts from Samoa, American Samoa, and Aotearoa New Zealand. We identified a strong candidate causal variant at this locus, rs200884524—a stop-gain variant in 1 Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA; 2 Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; 3 Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, USA; 4 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA; 5 Department of Biochemistry, University of Otago, Dunedin, New Zealand; 6 Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH, USA; 7 Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; 8 Ng ati Porou Hauora Charitable Trust, Te Puia Springs, Tair awhiti East Coast, New Zealand; 9 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand; 10 Ministry of Health, Government of Samoa, Apia, Samoa; 11 Lutia i Puava ae Mapu i Fagalele, Apia, Samoa; 12 School of Medicine, National University of Samoa, Apia, Samoa; 13 Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand; 14 Department of Public Health, Government of American Samoa, Pago Pago, American Sa- moa; 15 Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 16 International Health Institute, Department of Epidemiology, Brown University, Providence, RI, USA; 17 Department of Anthropology, Brown University, Providence, RI, USA 18 Twitter: @jenccarlson 19 Lead contact *Correspondence: jnc35@pitt.edu https://doi.org/10.1016/j.xhgg.2022.100155. Human Genetics and Genomics Advances 4, 100155, January 12, 2023 1 Ó 2022 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).