TY - JOUR
T1 - Complement genes contribute sex-biased vulnerability in diverse disorders
AU - Kamitaki, Nolan
AU - Sekar, Aswin
AU - Handsaker, Robert E
AU - de Rivera, Heather
AU - Tooley, Katherine
AU - Morris, David L
AU - Taylor, Kimberly E
AU - Whelan, Christopher W
AU - Tombleson, Philip
AU - Loohuis, Loes M Olde
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium
A2 - Boehnke, Michael
A2 - Kimberly, Robert P
A2 - Kaufman, Kenneth M
A2 - Harley, John B
A2 - Langefeld, Carl D.
A2 - Seidman, Christine E.
A2 - Pato, Michele T.
A2 - Pato, Carlos N.
A2 - Ophoff, Roel A.
A2 - Graham, Robert R.
A2 - Criswell, Lindsey A.
A2 - Vyse, Timothy J.
A2 - McCarroll, Steven A.
A2 - Klovins, Janis
A2 - Ņikitina-Zaķe, Liene
N1 - Funding Information:
Acknowledgements This work was supported by the National Human Genome Research Institute (HG006855), the National Institute of Mental Health (MH112491, MH105641, MH105653), the Stanley Center for Psychiatric Research, and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) at Guy’s and St Thomas’ NHS Foundation and King’s College London. We thank C. Usher and C. Patil for contributions to the figures and manuscript text, and M. Florio for suggestions regarding figure display.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/25
Y1 - 2020/6/25
N2 - 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.
AB - 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.
KW - Adult
KW - Alleles
KW - Complement C3/analysis
KW - Complement C4/analysis
KW - Female
KW - Genetic Predisposition to Disease
KW - HLA Antigens/genetics
KW - Haplotypes
KW - Humans
KW - Lupus Erythematosus, Systemic/blood
KW - Major Histocompatibility Complex/genetics
KW - Male
KW - Middle Aged
KW - Sex Characteristics
KW - Sjogren's Syndrome/blood
KW - Young Adult
UR - http://www.scopus.com/inward/record.url?scp=85086580754&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2277-x
DO - 10.1038/s41586-020-2277-x
M3 - Article
C2 - 32499649
SN - 0028-0836
VL - 582
SP - 577
EP - 581
JO - Nature
JF - Nature
IS - 7813
ER -