Decoding the diversity of killer immunoglobulin-like receptors by deep sequencing and a high-resolution imputation method

Saori Sakaue; Kazuyoshi Hosomichi; Jun Hirata; Hirofumi Nakaoka; Keiko Yamazaki; Makoto Yawata; Nobuyo Yawata; Tatsuhiko Naito; Junji Umeno; Takaaki Kawaguchi; Toshiyuki Matsui; Satoshi Motoya; Yasuo Suzuki; Hidetoshi Inoko; Atsushi Tajima; Takayuki Morisaki; Koichi Matsuda; Yoichiro Kamatani; Kazuhiko Yamamoto; Ituro Inoue; Yukinori Okada

doi:10.1016/j.xgen.2022.100101

Decoding the diversity of killer immunoglobulin-like receptors by deep sequencing and a high-resolution imputation method

Cell Genom. 2022 Mar 9;2(3):100101. doi: 10.1016/j.xgen.2022.100101.

Authors

Saori Sakaue^{1

2

3

4

5}, Kazuyoshi Hosomichi⁶, Jun Hirata¹, Hirofumi Nakaoka⁷, Keiko Yamazaki^{8

9

10}, Makoto Yawata^{11

12

13

14}, Nobuyo Yawata^{15

16

17}, Tatsuhiko Naito^{1

18}, Junji Umeno¹⁹, Takaaki Kawaguchi²⁰, Toshiyuki Matsui²¹, Satoshi Motoya²², Yasuo Suzuki²³, Hidetoshi Inoko²⁴, Atsushi Tajima⁶, Takayuki Morisaki²⁵, Koichi Matsuda²⁶, Yoichiro Kamatani^{5

27}, Kazuhiko Yamamoto¹⁰, Ituro Inoue⁷, Yukinori Okada^{1

28

29

30

31}

Affiliations

¹ Department of Statistical Genetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
² Center for Data Sciences, Harvard Medical School, Boston, MA 02115, USA.
³ Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
⁶ Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.
⁷ Human Genetics Laboratory, National Institute of Genetics, Shizuoka 411-8540, Japan.
⁸ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
⁹ Department of Public Health, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
¹⁰ Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
¹¹ Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, and National University Health System, Singapore 119228, Singapore.
¹² NUSMed Immunology Translational Research Programme, and Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore.
¹³ Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore 117609, Singapore.
¹⁴ International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
¹⁵ Department of Ocular Pathology and Imaging Science, Kyushu University, 812-8582, Japan.
¹⁶ Singapore Eye Research Institute, Singapore 169856, Singapore.
¹⁷ Duke-NUS Medical School, Singapore 169857, Singapore.
¹⁸ Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
¹⁹ Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
²⁰ Division of Gastroenterology, Department of Medicine, Tokyo Yamate Medical Center, Tokyo 169-0073, Japan.
²¹ Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka 818-0067, Japan.
²² Department of Gastroenterology, Sapporo-Kosei General Hospital, Sapporo 060-0033, Japan.
²³ Department of Internal Medicine, Faculty of Medicine, Toho University, Chiba 274-8510, Japan.
²⁴ GenoDive Pharma Inc., Atsugi 243-0018, Japan.
²⁵ Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
²⁶ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan.
²⁷ Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan.
²⁸ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita 565-0871, Japan.
²⁹ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita 565-0871, Japan.
³⁰ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
³¹ Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita 565-0871, Japan.

Abstract

The killer cell immunoglobulin-like receptor (KIR) recognizes human leukocyte antigen (HLA) class I molecules and modulates the function of natural killer cells. Despite its role in immunity, the complex genomic structure has limited a deep understanding of the KIR genomic landscape. Here we conduct deep sequencing of 16 KIR genes in 1,173 individuals. We devise a bioinformatics pipeline incorporating copy number estimation and insertion or deletion (indel) calling for high-resolution KIR genotyping. We define 118 alleles in 13 genes and demonstrate a linkage disequilibrium structure within and across KIR centromeric and telomeric regions. We construct a KIR imputation reference panel (n_reference = 689, imputation accuracy = 99.7%), apply it to biobank genotype (n_total = 169,907), and perform phenome-wide association studies of 85 traits. We observe a dearth of genome-wide significant associations, even in immune traits implicated previously to be associated with KIR (the smallest p = 1.5 × 10^-4). Our pipeline presents a broadly applicable framework to evaluate innate immunity in large-scale datasets.

Keywords: KIR; PheWAS; biobank; immunogenetics; imputation; killer cell immunoglobulin-like receptor; next-generation sequencing; target sequencing.