Depression in multiple sclerosis patients associated with risk variant near NEGR1

Steven W Brugger; M Cannon Gardner; Jeremy T Beales; Farren Briggs; Mary F Davis

doi:10.1016/j.msard.2020.102537

Depression in multiple sclerosis patients associated with risk variant near NEGR1

Mult Scler Relat Disord. 2020 Nov:46:102537. doi: 10.1016/j.msard.2020.102537. Epub 2020 Oct 4.

Authors

Steven W Brugger¹, M Cannon Gardner¹, Jeremy T Beales¹, Farren Briggs², Mary F Davis³

Affiliations

¹ Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States.
² Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States.
³ Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States; Department Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States. Electronic address: mary_davis@byu.edu.

PMID: 33296963
DOI: 10.1016/j.msard.2020.102537

Abstract

Background: A substantial number of patients diagnosed with multiple sclerosis (MS) suffer from depression in addition to physical symptoms and disability. Recent evidence suggests a stronger relationship may exist between MS and depression than previously thought, in which a diagnosis of depression may be prodromic to the development of MS.

Methods: A genome-wide association study (GWAS) was performed to identify genetic variants associated with the development of depression in a cohort of MS patients. The control group (n = 1180) was composed of MS patients with no diagnoses of depression as determined by ICD-9 and ICD-10 billing codes present in the electronic health record (EHR). Separate analyses were performed for three different case groups: 1) MS patients having a depression diagnosis at any time (n = 182), 2) MS patients having a depression diagnosis one year pre-MS diagnosis (n = 27), and 3) MS patients having a depression diagnosis one year post-MS diagnosis (n = 130). Logistic regression analyses were also performed to test for associations between the development of depression and an APOE tagging variant, as APOE was previously linked to depressive affect in MS. An additional logistic regression analysis tested for associations between depression in MS patients and SNPs associated with depression in the general population. Pathway enrichment analyses were also conducted to identify pathways that link the two diseases.

Results: GWAS identified no novel associations between variants and a diagnosis of depression relative to a diagnosis of MS. One variant, rs1432639, associated with depression in the general population, was significantly associated with the development of depression post-MS diagnosis. The APOE-related SNPs were not associated with depression in this study population. An IGF1 pathway approached statistical significance in patients diagnosed with depression prior to a diagnosis of MS.

Conclusion: rs1432639 and the IGF1 pathway provide evidence for a genetic link between MS and depression that warrants further research.

Keywords: Depression; GWAS; Multiple sclerosis; Pathway analysis; Polymorphism.

MeSH terms

Cell Adhesion Molecules, Neuronal
Cohort Studies
Depression / epidemiology
Depression / genetics
GPI-Linked Proteins
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Multiple Sclerosis* / complications
Multiple Sclerosis* / epidemiology
Multiple Sclerosis* / genetics
Polymorphism, Single Nucleotide / genetics

Substances

Cell Adhesion Molecules, Neuronal
GPI-Linked Proteins
NEGR1 protein, human