Struan F.A. Grant
· Professor of Pediatrics (Human Genetics)University of Pennsylvania · Rehabilitation Medicine
Active 1973–2024
About
Struan F.A. Grant, PhD, is a Professor of Pediatrics (Human Genetics) at the Perelman School of Medicine, University of Pennsylvania, and holds the Daniel B. Burke Endowed Chair for Diabetes Research at the Children's Hospital of Philadelphia. He is also the Director of the Center for Spatial and Functional Genomics at the Children's Hospital of Philadelphia. Dr. Grant has been conducting human genomics research for over 25 years, with notable contributions including the discovery of the polymorphic Sp1 site in the COL1A1 gene and its association with osteoporosis, as well as the identification of variation in the TCF7L2 gene that plays a key role in conferring risk for type 2 diabetes. He has also led efforts in international genetics to characterize genes influencing birth weight and childhood obesity, and has contributed to uncovering genes involved in traits such as inflammatory bowel disease, autism, and type 1 diabetes. His current research primarily focuses on investigating disease genomics with a specific emphasis on pediatrics. Utilizing high-throughput genotyping and sequencing technologies, along with statistical and bioinformatic approaches, Dr. Grant aims to unravel the genomic architecture of complex traits such as childhood obesity, pediatric bone strength, diabetes, and sleep. His work is driven by the understanding that these phenotypes are strongly influenced by genetic factors, and that studying them in children can reduce environmental confounding factors. His research has significant implications for disease prevention and reducing societal and individual morbidity, especially given the global prevalence of these conditions.
Research topics
- Genetics
- Biology
- Medicine
- Internal medicine
- Computational biology
- Evolutionary biology
- Computer Science
- Environmental health
- Bioinformatics
- Demography
- Endocrinology
Selected publications
Nature Genetics · 2022 · 188 citations
- Biology
- Internal medicine
- Genetics
A saturated map of common genetic variants associated with human height
Nature · 2022 · 877 citations
- Genetics
- Biology
- Evolutionary biology
) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
New insights into the genetic etiology of Alzheimer’s disease and related dementias
Nature Genetics · 2022 · 2403 citations
- Biology
- Genetics
- Bioinformatics
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
The power of genetic diversity in genome-wide association studies of lipids
Nature · 2021 · 1032 citations
- Biology
- Genetics
- Evolutionary biology
Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients
The Journal of Experimental Medicine · 2021 · 73 citations
- Computer Science
- Computer Science
- Genetics
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits
PLoS Genetics · 2020 · 229 citations
- Biology
- Genetics
- Demography
The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
Nature Communications · 2020 · 86 citations
- Genetics
- Biology
- Computational biology
). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.
Recent grants
NIH · $462k · 2019
Elucidation of Genetic Effects on Sleep and Circadian Traits
NIH · $3.6M · 2018–2023
Genome Wide Association Study for Childhood Obesity
NIH · $9.5M · 2008–2026
Variant to gene mapping for Alzheimer's Disease
NIH · $3.5M · 2017–2024
NIH · $3.4M · 2020
Frequent coauthors
- 1248 shared
Jun Liu
Suzhou University of Science and Technology
- 1156 shared
Wei Zhao
Michigan United
- 930 shared
Zhe Wang
Zhejiang University
- 903 shared
Jun Liu
University of California, San Francisco
- 802 shared
Wei Zhou
XinHua Hospital
- 740 shared
Wei Zhou
Yanbian University
- 669 shared
Håkon Håkonarson
University of Pennsylvania
- 600 shared
Wei Huang
China Textile Academy
Education
- 1991
B.S., Genetics
University of Aberdeen, UK
- 1996
Ph.D., Genetics
University of Aberdeen, UK
Awards & honors
- Daniel B. Burke Endowed Chair for Diabetes Research
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