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Genes Immun. 2018 Nov 21. doi: 10.1038/s41435-018-0051-y. [Epub ahead of print]

Unfolding of hidden white blood cell count phenotypes for gene discovery using latent class mixed modeling.

Author information

1
Department of Biomedical Informatics Medical Education, School of Medicine, University of Washington, Seattle, WA, 98109, USA. tohall@uw.edu.
2
Department of Biomedical Informatics Medical Education, School of Medicine, University of Washington, Seattle, WA, 98109, USA.
3
Kaiser Permanente Washington Health Research Institute (Formerly Group Health Cooperative-Seattle), Kaiser Permanente, Seattle, WA, 98109, USA.
4
Departments of Biomedical Informatics and Medicine, Vanderbilt University, Nashville, TN, 37235, USA.
5
Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
6
Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, WI, 54449, USA.
7
Geisinger Research, Rockville, MD, 20850, USA.
8
Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA, 98105, USA.
9
Department of Biomedical Informatics Medical Education, School of Medicine, University of Washington, Seattle, WA, 98109, USA. davidcr@uw.edu.

Abstract

Resting-state white blood cell (WBC) count is a marker of inflammation and immune system health. There is evidence that WBC count is not fixed over time and there is heterogeneity in WBC trajectory that is associated with morbidity and mortality. Latent class mixed modeling (LCMM) is a method that can identify unobserved heterogeneity in longitudinal data and attempts to classify individuals into groups based on a linear model of repeated measurements. We applied LCMM to repeated WBC count measures derived from electronic medical records of participants of the National Human Genetics Research Institute (NHRGI) electronic MEdical Record and GEnomics (eMERGE) network study, revealing two WBC count trajectory phenotypes. Advancing these phenotypes to GWAS, we found genetic associations between trajectory class membership and regions on chromosome 1p34.3 and chromosome 11q13.4. The chromosome 1 region contains CSF3R, which encodes the granulocyte colony-stimulating factor receptor. This protein is a major factor in neutrophil stimulation and proliferation. The association on chromosome 11 contain genes RNF169 and XRRA1; both involved in the regulation of double-strand break DNA repair.

PMID:
30459343
DOI:
10.1038/s41435-018-0051-y

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