Kyle Walsh

Overview:

Dr. Walsh is Associate Professor of Neurosurgery and Pathology, Director of the Division of Neuro-epidemiology, and a Senior Fellow in the Duke Center for the Study of Aging and Human Development. He leads Duke’s Neuro-epidemiology Lab, which integrates bench science with statistical methods to study the neurobiology of glial senescence and gliomagenesis. This research interrogates human genomic and epigenomic profiles to identify both heritable and modifiable factors that contribute to neurologic and physical decline, applying these approaches to studying the shared neurobiology of cognition, glial senescence, and gliomagenesis. The lab has a long history studying telomere maintenance in pre-malignant cells and its role in the development of cancer, most notably glioblastoma.

Positions:

Associate Professor in Neurosurgery

Neurosurgery
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Associate Professor in Pediatrics

Pediatrics, Children's Health Discovery Institute
School of Medicine

Associate Professor in Population Health Sciences

Population Health Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2011

Yale University School of Medicine

Grants:

My Childhood Cancer: Survey Series

Administered By
Neurosurgery
Awarded By
Alex's Lemonade Stand
Role
Principal Investigator
Start Date
End Date

Genetic Susceptibility to Pediatric Glioma in Individuals and Diverse populations

Administered By
Neurosurgery
Awarded By
University of Southern California
Role
Principal Investigator
Start Date
End Date

The role of rare and common variants in genetic predisposition to medulloblastoma

Administered By
Neurosurgery
Awarded By
Sontag Foundation
Role
Principal Investigator
Start Date
End Date

Genetic Susceptibility to pediatric Osteosarcoma and Interaction with Measures of Childhood Growth

Administered By
Neurosurgery
Awarded By
Alex's Lemonade Stand
Role
Principal Investigator
Start Date
End Date

Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life ALL Development

Administered By
Pediatrics, Children's Health Discovery Institute
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition.

Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms (SNPs) that increase late-onset Alzheimer's disease (LOAD) risk. To identify additional LOAD-associated variants and provide insight into underlying disease biology, we performed a phenome-wide association study on 23 known LOAD-associated SNPs and 4:1 matched control SNPs using UK Biobank data. LOAD-associated SNPs were significantly enriched for associations with 8/778 queried traits, including 3 platelet traits. The strongest enrichment was for platelet distribution width (PDW) (p = 1.2 × 10-5), but increased PDW was not associated with LOAD susceptibility in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk (17,008 cases; 37,154 controls) and 5 survived false-discovery rate correction. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in epidermal growth factor receptor. Integrating GWAS and phenome-wide association study data reveals substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicates epidermal growth factor receptor - a mediator of β-amyloid toxicity - in Alzheimer's disease susceptibility.
Authors
Khaire, AS; Wimberly, CE; Semmes, EC; Hurst, JH; Walsh, KM
MLA Citation
Khaire, Archita S., et al. “An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition.Neurobiol Aging, vol. 118, Oct. 2022, pp. 117–23. Pubmed, doi:10.1016/j.neurobiolaging.2022.05.011.
URI
https://scholars.duke.edu/individual/pub1522365
PMID
35715361
Source
pubmed
Published In
Neurobiol Aging
Volume
118
Published Date
Start Page
117
End Page
123
DOI
10.1016/j.neurobiolaging.2022.05.011

Assisted reproductive technology and association with childhood cancer subtypes.

OBJECTIVES: To investigate the association between assisted reproductive technology (ART) use and childhood cancer subtype. STUDY DESIGN: We deployed a cross-sectional survey of 1701 parents of children with cancer about their ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use, birthweight and multiple gestation status with childhood cancer, by subtype. RESULTS: ART use was highest among children with osteosarcoma relative to children with other cancer types, and this association was statistically significant in multivariable models (OR = 4.4; 95% CI = 1.7-11.3; p = 0.0020). ART use was also elevated among children with hepatoblastoma, but this relationship appeared to be due to the strong associations between ART use and lower birthweight in our sample. No specific ART modality appeared to drive these associations. In univariate models, multiple gestation was associated with a 2.7-fold increased odds of hepatoblastoma (OR = 2.71; 95% CI = 1.14-6.42; p = 0.02) and a 1.6-fold increased odds of neuroblastoma (OR = 1.62; 95% CI = 1.03-2.54; p = 0.03), but these associations were not retained in multivariable models. CONCLUSIONS: Associations between ART use and hepatoblastoma risk may be attributable to birthweight, a known hepatoblastoma risk factor. ART use may also be associated with osteosarcoma, independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long-term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.
Authors
Gulrajani, NB; Montes, S; McGough, D; Wimberly, CE; Khattab, A; Semmes, EC; Towry, L; Cohen, JL; Hurst, JH; Landi, D; Hill, SN; Walsh, KM
MLA Citation
Gulrajani, Natalie B., et al. “Assisted reproductive technology and association with childhood cancer subtypes.Cancer Med, Aug. 2022. Pubmed, doi:10.1002/cam4.5114.
URI
https://scholars.duke.edu/individual/pub1532289
PMID
35929579
Source
pubmed
Published In
Cancer Medicine
Published Date
DOI
10.1002/cam4.5114

Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer.

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.
Authors
Byun, J; Han, Y; Li, Y; Xia, J; Long, E; Choi, J; Xiao, X; Zhu, M; Zhou, W; Sun, R; Bossé, Y; Song, Z; Schwartz, A; Lusk, C; Rafnar, T; Stefansson, K; Zhang, T; Zhao, W; Pettit, RW; Liu, Y; Li, X; Zhou, H; Walsh, KM; Gorlov, I; Gorlova, O; Zhu, D; Rosenberg, SM; Pinney, S; Bailey-Wilson, JE; Mandal, D; de Andrade, M; Gaba, C; Willey, JC; You, M; Anderson, M; Wiencke, JK; Albanes, D; Lam, S; Tardon, A; Chen, C; Goodman, G; Bojeson, S; Brenner, H; Landi, MT; Chanock, SJ; Johansson, M; Muley, T; Risch, A; Wichmann, H-E; Bickeböller, H; Christiani, DC; Rennert, G; Arnold, S; Field, JK; Shete, S; Le Marchand, L; Melander, O; Brunnstrom, H; Liu, G; Andrew, AS; Kiemeney, LA; Shen, H; Zienolddiny, S; Grankvist, K; Johansson, M; Caporaso, N; Cox, A; Hong, Y-C; Yuan, J-M; Lazarus, P; Schabath, MB; Aldrich, MC; Patel, A; Lan, Q; Rothman, N; Taylor, F; Kachuri, L; Witte, JS; Sakoda, LC; Spitz, M; Brennan, P; Lin, X; McKay, J; Hung, RJ; Amos, CI
MLA Citation
Byun, Jinyoung, et al. “Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer.Nature Genetics, vol. 54, no. 8, Aug. 2022, pp. 1167–77. Epmc, doi:10.1038/s41588-022-01115-x.
URI
https://scholars.duke.edu/individual/pub1531644
PMID
35915169
Source
epmc
Published In
Nature Genetics
Volume
54
Published Date
Start Page
1167
End Page
1177
DOI
10.1038/s41588-022-01115-x

Influence of county-level geographic/ancestral origin on glioma incidence and outcomes in US Hispanics.

PURPOSE: Glioma incidence is 25% lower in Hispanics than White non-Hispanics. The U.S. Hispanic population is diverse, and registry-based analyses may mask incidence differences associated with geographic/ancestral origins. METHODS: County-level glioma incidence data in Hispanics were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS). American Community Survey data were used to determine county-level proportion of the Hispanic population of Mexican/Central-American origin and of Caribbean origin. Age-adjusted incidence rate-ratios and incidence rate ratios (IRRs) quantified the glioma incidence differences across groups. State-level estimates of admixture in Hispanics were obtained from published 23andMe data. RESULTS: Compared to predominantly Caribbean-origin counties, predominantly Mexican/Central-American-origin counties had lower age-adjusted risks of glioma (IRR=0.83; P<0.0001), glioblastoma (IRR=0.86; P<0.0001), diffuse/anaplastic astrocytoma (IRR=0.78; P<0.0001), oligodendroglioma (IRR=0.82; P<0.0001), ependymoma (IRR=0.88; P=0.012), and pilocytic astrocytoma (IRR=0.76; P<0.0001). Associations were consistent in children and adults, and using more granular geographic regions. Despite having lower glioma incidence, Hispanic glioblastoma patients from predominantly Mexican/Central-American-origin counties had poorer survival than Hispanics living in predominantly Caribbean-origin counties. Incidence and survival differences could be partially explained by state-level estimates of European admixture in Hispanics, with European admixture associated with higher incidence and improved survival. CONCLUSIONS: Glioma incidence and outcomes differ in association with the geographic origins of Hispanic communities, with counties of predominantly Mexican/Central-American-origin at significantly reduced risk and those of Caribbean-origin at comparatively greater risk. Although typically classified as a single ethnic group, appreciating the cultural, socioeconomic, and genetic diversity of Hispanics can advance cancer disparities research.
Authors
Walsh, KM; Neff, C; Bondy, ML; Kruchko, C; Huse, JT; Amos, CI; Barnholtz-Sloan, JS; Ostrom, QT
MLA Citation
Walsh, Kyle M., et al. “Influence of county-level geographic/ancestral origin on glioma incidence and outcomes in US Hispanics.Neuro Oncol, July 2022. Pubmed, doi:10.1093/neuonc/noac175.
URI
https://scholars.duke.edu/individual/pub1529283
PMID
35868246
Source
pubmed
Published In
Neuro Oncol
Published Date
DOI
10.1093/neuonc/noac175

Accelerated epigenetic aging in newborns with Down syndrome.

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p < 0.0001), with an epigenetic age acceleration of 244 days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196-292 days). We also found evidence of epigenetic age acceleration associated with somatic GATA1 mutations among newborns with DS (p = 0.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging-related traits in DS.
Authors
Xu, K; Li, S; Muskens, IS; Elliott, N; Myint, SS; Pandey, P; Hansen, HM; Morimoto, LM; Kang, AY; Ma, X; Metayer, C; Mueller, BA; Roberts, I; Walsh, KM; Horvath, S; Wiemels, JL; de Smith, AJ
MLA Citation
Xu, Keren, et al. “Accelerated epigenetic aging in newborns with Down syndrome.Aging Cell, vol. 21, no. 7, July 2022, p. e13652. Pubmed, doi:10.1111/acel.13652.
URI
https://scholars.duke.edu/individual/pub1524964
PMID
35661546
Source
pubmed
Published In
Aging Cell
Volume
21
Published Date
Start Page
e13652
DOI
10.1111/acel.13652

Research Areas:

Muser Mentor