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Genome-wide variants and polygenic risk scores for cognitive impairment following blood or marrow transplantation

Bone Marrow Transplantation volume 57, pages 925–933 (2022)Cite this article

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Abstract

Cognitive impairment is prevalent in blood or marrow transplantation (BMT) recipients, albeit with inter-individual variability. We conducted a genome-wide association study of objective cognitive function assessed longitudinally in 239 adult BMT recipients for discovery and replicated in an independent cohort of 540 BMT survivors. Weighted genome-wide polygenic risk scores (PRS) were constructed using linkage disequilibrium pruned significant SNPs. Forty-four genome-wide significant SNPs were identified using additive (n = 3); codominant (n = 20) and genotype models (n = 21). Each additional copy of a risk allele was associated with a 0.28-point (p = 1.07 × 10−8) to a 1.82-point (p = 6.7 × 10−12) increase in a global deficit score. We replicated two SNPs (rs11634183 and rs12486041) with links to neural integrity. Patients in the top PRS quintile were at increased risk of cognitive impairment in discovery (RR = 1.95, 95%CI: 1.28–2.96, p = 0.002) and replication cohorts (OR = 1.84, 95%CI, 1.02–3.32, p = 0.043). Associations were stronger among individuals with lowest clinical risk for cognitive impairment. These findings support potential utility of PRS-based risk classification in the development of targeted interventions aimed at improving cognitive outcomes in BMT survivors.

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Fig. 1: Manhattan plots of significant GWAS SNPs associated with post-BMT GDS in the discovery cohort.
Fig. 2: Association of post-BMT GDS with PRS categories.

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Data availability

The data underlying this article cannot be shared publicly for the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding authors.

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Acknowledgements

The authors thank Emily Morse, Molly Mather, and Canlan Sun for their roles in the data collection and patient management of the discovery cohort at City of Hope.

Funding

This work was supported in part by research funding from the Leukemia andLymphoma Society (LLS) (62771-11) to SB and LLS Career Development Award (3386-19) to NS. NS is also supported by the National Marrow Donor Program Be The Match Foundation.

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Authors and Affiliations

  1. Institute for Cancer Outcomes and Survivorship, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Noha Sharafeldin, Purnima Singh, Yanjun Chen, Liton Francisco & Smita Bhatia

  2. Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

    Jianqing Zhang & Akinyemi I. Ojesina

  3. Population Sciences, City of Hope, Duarte, CA, USA

    Alysia Bosworth, Sunita K. Patel & F. Lennie Wong

  4. Department of Mathematics, University of North Texas, Denton, TX, USA

    Xuexia Wang

  5. Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA

    Stephen J. Forman

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  1. Noha Sharafeldin
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Contributions

SB constructed the study cohort and SB, NS, SP, SJF contributed to the study design. AB, LF collected, maintained, and stored the data. NS, YJ, XW, and FLW prepared the data for analysis. PS handled and processed the genetic samples. NS designed and performed the statistical data analysis. NS, JZ, AIO, and SB interpreted the genetic results. NS and SB drafted the manuscript with critical revisions from all authors.

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Correspondence to Noha Sharafeldin or Smita Bhatia.

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Sharafeldin, N., Zhang, J., Singh, P. et al. Genome-wide variants and polygenic risk scores for cognitive impairment following blood or marrow transplantation. Bone Marrow Transplant 57, 925–933 (2022). https://doi.org/10.1038/s41409-022-01642-5

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