Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity
Cell Genomics, 2025
Sonehara K., Uwamino Y., Saiki R., Takeshita M., Namba S., Uno S., Nakanishi T., Nishimura T., Naito T., Sato G., Kanai M., Liu A., Uchida S., Kurafuji T., Tanabe A., Arai T., Ohno A., Shibata A., Tanaka S., Wakui M., Kashimura S., Tomi C., Hara A., Yoshikawa S., Gotanda K., Misawa K., Tanaka H., Azekawa S., Wang Q., Edahiro R., Shirai Y., Yamamoto K., Nagao G., Suzuki T., Kiyoshi M., Ishii-Watabe A., Higashiue S., Kobayashi S., Yamaguchi H., Okazaki Y., Matsumoto N., Masumoto A., Koga H., Kanai A., Oda Y., Suzuki Y., Matsuda K., Kitagawa Y., Koike R., Kimura A., Kumanogoh A., Yoshimura A., Imoto S., Miyano S., Kanai T., Fukunaga K., Hasegawa N., Murata M., Matsushita H., Ogawa S., Okada Y., Namkoong H.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Infectious Diseases | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Vaccine immunogenicity is influenced by the vaccinee’s genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = −0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves’ disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.