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To understand the sex difference in the genetic architecture of HM, which may contribute to understanding HM aetiology and help further the realisation of precision medicine for HM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed sex-stratified exome-wide association studies (ExWAS) with n (males)=7492\u2009and n (females)=8090, along with gene- and pathway-based tests and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to HM in a sex-specific manner.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In our ExWAS, we identified that a male-specific gene,\n                      <jats:italic>CHRNB1<\/jats:italic>\n                      (Z\n                      <jats:sub>females<\/jats:sub>\n                      =1.382, P\n                      <jats:sub>females<\/jats:sub>\n                      =0.083; Z\n                      <jats:sub>males<\/jats:sub>\n                      =4.029, P\n                      <jats:sub>males<\/jats:sub>\n                      =2.80\u00d710\n                      <jats:sup>\u221205<\/jats:sup>\n                      ; P\n                      <jats:sub>difference<\/jats:sub>\n                      =0.003), was associated with higher risk scores of HM in males than in females. Rare variant burden tests showed a significant excess of rare protein-truncating variants among HM males in\n                      <jats:italic>CHRNB1<\/jats:italic>\n                      -related pathways, including cell-cell signalling and muscle structure development. Sex-based differences in gene expression within\n                      <jats:italic>CHRNB1<\/jats:italic>\n                      -enriched ciliary body cells were observed; specifically, increased expression of mitochondrial metabolism-related genes in males and antioxidant genes in females. Functional differences in mitochondrial metabolism were confirmed in male-derived H1 and female-derived H9 human embryonic stem cell lines, with H1 cells specifically exhibiting significant dysregulation of mitochondrial organisation and mitochondrial respiratory chain complex assembly after\n                      <jats:italic>CHRNB1<\/jats:italic>\n                      knockdown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Together, our study provides insight into the sex differences in the genetic architecture of HM and highlights\n                      <jats:italic>CHRNB1<\/jats:italic>\n                      \u2019s role in HM pathogenesis in males.\n                    <\/jats:p>\n                  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