Complement genes contribute sex-biased vulnerability in diverse disorders

Nolan Kamitaki (), Aswin Sekar, Robert E. Handsaker, Heather Rivera, Katherine Tooley, David L. Morris, Kimberly E. Taylor, Christopher W. Whelan, Philip Tombleson, Loes M. Olde Loohuis, Michael Boehnke, Robert P. Kimberly, Kenneth M. Kaufman, John B. Harley, Carl D. Langefeld, Christine E. Seidman, Michele T. Pato, Carlos N. Pato, Roel A. Ophoff, Robert R. Graham, Lindsey A. Criswell, Timothy J. Vyse () and Steven A. McCarroll ()
Additional contact information
Nolan Kamitaki: Harvard Medical School
Aswin Sekar: Harvard Medical School
Robert E. Handsaker: Harvard Medical School
Heather Rivera: Harvard Medical School
Katherine Tooley: Harvard Medical School
David L. Morris: King’s College London
Kimberly E. Taylor: UCSF School of Medicine
Christopher W. Whelan: Harvard Medical School
Philip Tombleson: King’s College London
Loes M. Olde Loohuis: University of California
Michael Boehnke: University of Michigan
Robert P. Kimberly: University of Alabama at Birmingham
Kenneth M. Kaufman: Cincinnati Children’s Medical Center & University of Cincinnati and the US Department of Veterans Affairs Medical Center
John B. Harley: Cincinnati Children’s Medical Center & University of Cincinnati and the US Department of Veterans Affairs Medical Center
Carl D. Langefeld: Wake Forest School of Medicine
Christine E. Seidman: Harvard Medical School
Michele T. Pato: SUNY Downstate Medical Center
Carlos N. Pato: SUNY Downstate Medical Center
Roel A. Ophoff: University of California
Robert R. Graham: Genentech
Lindsey A. Criswell: UCSF School of Medicine
Timothy J. Vyse: King’s College London
Steven A. McCarroll: Harvard Medical School

Nature, 2020, vol. 582, issue 7813, 577-581

Abstract: Abstract Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Date: 2020
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DOI: 10.1038/s41586-020-2277-x

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