Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci

Ece Bayram; Paolo Reho; Irene Litvan; International LBD Genomics Consortium; Jinhui Ding; J Raphael Gibbs; Clifton L Dalgard; Bryan J Traynor; Sonja W Scholz; Ruth Chia

doi:10.1038/s41531-024-00649-7

Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci

NPJ Parkinsons Dis. 2024 Feb 20;10(1):39. doi: 10.1038/s41531-024-00649-7.

Authors

Ece Bayram¹, Paolo Reho², Irene Litvan¹; International LBD Genomics Consortium; Jinhui Ding³, J Raphael Gibbs³, Clifton L Dalgard^{4

5}, Bryan J Traynor^{6

7

8}, Sonja W Scholz^{2

6}, Ruth Chia⁹

Affiliations

¹ Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California San Diego, La Jolla, CA, USA.
² Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
³ Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁴ Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵ The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁶ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁷ Neuromuscular Diseases Research Section, National Institute on Aging, Bethesda, MD, USA.
⁸ Therapeutics Development Laboratory, National Center for Advancing Translational Sciences, Rockville, MD, USA.
⁹ Neuromuscular Diseases Research Section, National Institute on Aging, Bethesda, MD, USA. ruth.chia@nih.gov.

Abstract

Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65-3.56, p-value = 7.0 × 10^-6) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10^-4). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer's-related risk for females with LBD.

Grants and funding

K99 AG073453/AG/NIA NIH HHS/United States