Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

Nathan Nakatsuka^{1

2}, Nick Patterson^{3

4}, Nikolaos A Patsopoulos^{4

5

6}, Nicolas Altemose⁷, Arti Tandon^{8

4}, Ashley H Beecham⁹, Jacob L McCauley^{9

10}, Noriko Isobe^{11

12}, Stephen Hauser¹¹, Philip L De Jager^{4

13}, David A Hafler^{4

14}, Jorge R Oksenberg¹¹, David Reich^{15

16

17

18}

Affiliations

¹ Department of Genetics, Harvard Medical School, New Research Building, Boston, MA, 02115, USA. nathan_nakatsuka@hms.harvard.edu.
² Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, 02115, USA. nathan_nakatsuka@hms.harvard.edu.
³ Department of Human Evolutionary Biology, Harvard University, 16 Divinity Ave., Cambridge, MA, 02138, USA.
⁴ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 02141, USA.
⁵ Systems Biology and Computer Science Program, Department of Neurology, Ann Romney Center for Neurological Diseases, Brigham & Women's Hospital, Boston, MA, 02115, USA.
⁶ Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Bioengineering, University of California Berkeley, San Francisco, Berkeley, CA, 94720, USA.
⁸ Department of Genetics, Harvard Medical School, New Research Building, Boston, MA, 02115, USA.
⁹ John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
¹⁰ Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
¹¹ Department of Neurology, University of California San Francisco School of Medicine, San Francisco, CA, 94158, USA.
¹² Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, 812-8582, Japan.
¹³ Department of Neurology, Center for Translational & Computational Neuroimmunology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
¹⁴ Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, 06520, USA.
¹⁵ Department of Genetics, Harvard Medical School, New Research Building, Boston, MA, 02115, USA. reich@genetics.med.harvard.edu.
¹⁶ Department of Human Evolutionary Biology, Harvard University, 16 Divinity Ave., Cambridge, MA, 02138, USA. reich@genetics.med.harvard.edu.
¹⁷ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 02141, USA. reich@genetics.med.harvard.edu.
¹⁸ Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, 02115, USA. reich@genetics.med.harvard.edu.

PMID: 33037294
PMCID: PMC7547691
DOI: 10.1038/s41598-020-74035-7

Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

Nathan Nakatsuka et al. Sci Rep. 2020.

. 2020 Oct 9;10(1):16902.

doi: 10.1038/s41598-020-74035-7.

Authors

Affiliations

¹ Department of Genetics, Harvard Medical School, New Research Building, Boston, MA, 02115, USA. nathan_nakatsuka@hms.harvard.edu.
² Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, 02115, USA. nathan_nakatsuka@hms.harvard.edu.
³ Department of Human Evolutionary Biology, Harvard University, 16 Divinity Ave., Cambridge, MA, 02138, USA.
⁴ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 02141, USA.
⁵ Systems Biology and Computer Science Program, Department of Neurology, Ann Romney Center for Neurological Diseases, Brigham & Women's Hospital, Boston, MA, 02115, USA.
⁶ Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Bioengineering, University of California Berkeley, San Francisco, Berkeley, CA, 94720, USA.
⁸ Department of Genetics, Harvard Medical School, New Research Building, Boston, MA, 02115, USA.
⁹ John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
¹⁰ Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
¹¹ Department of Neurology, University of California San Francisco School of Medicine, San Francisco, CA, 94158, USA.
¹² Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, 812-8582, Japan.
¹³ Department of Neurology, Center for Translational & Computational Neuroimmunology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
¹⁴ Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, 06520, USA.
¹⁵ Department of Genetics, Harvard Medical School, New Research Building, Boston, MA, 02115, USA. reich@genetics.med.harvard.edu.
¹⁶ Department of Human Evolutionary Biology, Harvard University, 16 Divinity Ave., Cambridge, MA, 02138, USA. reich@genetics.med.harvard.edu.
¹⁷ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 02141, USA. reich@genetics.med.harvard.edu.
¹⁸ Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, 02115, USA. reich@genetics.med.harvard.edu.

PMID: 33037294
PMCID: PMC7547691
DOI: 10.1038/s41598-020-74035-7

Abstract

Epidemiological studies have suggested differences in the rate of multiple sclerosis (MS) in individuals of European ancestry compared to African ancestry, motivating genetic scans to identify variants that could contribute to such patterns. In a whole-genome scan in 899 African-American cases and 1155 African-American controls, we confirm that African-Americans who inherit segments of the genome of European ancestry at a chromosome 1 locus are at increased risk for MS [logarithm of odds (LOD) = 9.8], although the signal weakens when adding an additional 406 cases, reflecting heterogeneity in the two sets of cases [logarithm of odds (LOD) = 2.7]. The association in the 899 individuals can be fully explained by two variants previously associated with MS in European ancestry individuals. These variants tag a MS susceptibility haplotype associated with decreased CD58 gene expression (odds ratio of 1.37; frequency of 84% in Europeans and 22% in West Africans for the tagging variant) as well as another haplotype near the FCRL3 gene (odds ratio of 1.07; frequency of 49% in Europeans and 8% in West Africans). Controlling for all other genetic and environmental factors, the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Two variants are sufficient to explain the admixture association signal. (A,B) Top GWAS variants in the region of the admixture association signal (red box) were taken and used in a logistic regression for genotype association on MS case–control status in African-American data after conditioning on global and local European ancestry. Y-axis is − log₁₀ (p-value) of association with MS case status. Shown in red are the most highly associated variants, rs12025416 in the *CD58* gene for (A) and rs6681271 in the *FCRL3* gene in (B) (after conditioning on the top variant in A). (C) Logistic regression of local European ancestry on case–control status in African-American data after controlling for global ancestry as a covariate as well as the top variants from (A,B). No conditioning indicates only controlling for global ancestry. The dotted line indicates threshold for significance (this p-value threshold represents a lower bound on significance due to the fact that the peak can shift after conditioning). The African-American data used for all analyses was the 2007 subset of the new cohort.

See this image and copyright information in PMC

References

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Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

Affiliations

Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical