Neil A. Hanchard, M.B.B.S., D.Phil.

Senior Investigator

Center for Precision Health Research

Head

Childhood Complex Disease Genomics Section

Education

M.B.B.S., University Of The West Indies

D.Phil., University Of Oxford

Pediatric Residency, Mayo Clinic, Minnesota

Medical Genetics Residency, Baylor College of Medicine, Houston, Texas

Contact Info

BG 50 RM 4907
50 SOUTH DR
BETHESDA MD 20892

Biography

Dr. Hanchard received his MD (MBBS with Honours) from the University of the West Indies in Kingston, Jamaica, after which he was award the Jamaica Rhodes Scholarship to the University of Oxford, UK. There, he completed a D.Phil. in Human Genetics and Clinical Medicine in the laboratory of Prof. Dominic Kwiatkowski, where he worked on population differentiation, genome variation, and natural selection in the Major Histocompatibility Complex. After returning to Jamaica to study sickle cell disease and severe childhood malnutrition as a clinical research scholar, he moved to the US to do his pediatric residency at the Mayo Clinic in Rochester, Minnesota, before completing a Medical Genetics fellowship at Baylor College of Medicine (BCM) in Houston, Texas. Soon after, he started his own lab as a tenure-track physician scientist in the Department of Molecular and Human genetics at BCM, focusing on the genetics of complex childhood diseases in diverse populations. In addition, Dr Hanchard cared for patients with rare genetic disorders and directed a medium throughput core genetics laboratory, in addition to mentoring and teaching graduate students, medical residents, and medical students. His research has provided insight to the population genetics of the mutation that causes sickle cell disease, identified novel genes in the development of congenital cardiovascular disorders and rare Mendelian disorders, and made inroads to understanding the pathogenesis of diabetic embryopathy, severe childhood malnutrition and transfusion alloimmunization in sickle cell disease.

Dr. Hanchard has served in multiple advisory positions for research institutions, the American Society for Human Genetics (ASHG), and genetics journals, and he was the first Early-Career board member of ASHG. He is a fellow of the American College of Medical Genetics and the Society for Pediatric Research. Dr. Hanchard is the current Chair of the Genome Analysis working group of the H3Africa Consortium and an NIH Distinguished Scholar.

Childhood Complex Disease Genomics Section

CCDGS Group Photo

The CCDGS is a translational genomics research lab using human genetics and genomics to better understand the pathophysiology of childhood diseases, particularly in diverse populations. Traditionally, genomic studies in children have focused on rare Mendelian phenotypes; however, the unique developmental context and reduced environmental exposure of children over time, provides fertile ground for genetic discovery and therapeutic investigation. At the same time, there is a general lack of diversity among genomic studies, with populations of African ancestry being particularly underrepresented, despite harboring an abundance of genomic diversity and unique clinical presentations. Our approach is to start with epidemiological evidence for differences between individuals and formulate plausible genetic models of disease. We then work with global and national collaborators to recruit well-phenotyped cohorts, to which we apply genomic, epigenomic, and transcriptomic technologies alongside population and quantitative genetics to identify the genes and gene-pathways that drive disease. Newly discovered genes are then validated, and the underlying mechanisms probed. This approach facilitates our ultimate goal of translating mechanistic understanding into therapeutic strategies – providing personalized medicine by going from bedside to bench and back.

The CCDGS Approach

Depiction of the CCDGS approach to translational genomics as a cycle that begins with epidemiological evidence and disease-model guided patient recruitment. The cycle continues to the application of genomic technologies to identify and validate genes of interest, and the cycle ends with findings being translated into therapeutic strategies for patients affected by the disease.

Projects

Childhood-onset Essential Hypertension (COEH)

Childhood-onset essential hypertension – in which there is elevated blood pressure in childhood without an obvious cause - affects 1-2% of all children, accounting for about 40% of all hypertension diagnoses in children, and is found more often among populations of African- or Hispanic ancestries. Children with COEH are difficult to diagnose, but tend to have a strong family history of hypertension. Although a role for genetics in the development of the disease has been supported, it is unclear whether this genetic risk mirrors that observed in adults (multiple genes all with small effects) or is more consistent with rare Mendelian diseases that are more striking in childhood (single genes with large effects). Crucially, the treatment of CEOH mirrors that of adults, partly because the underlying pathophysiology is assumed to be the same. We are exploring a model of Mendelian and rare variant contributions to COEH through cohort-based and natural-history gene-discovery coupled with functional characterization and consideration of existing pharmaceutical interventions [PMID: 38716726]. Our work includes working alongside national and international collaborators to expand our COEH cohort and better characterize the vascular and clinical phenotype of gene variant carriers.

Figure showing an individual with process of identifying rare protein-damaging variants. On the right, the image depicts the differences in vascular smooth muscle cells with and without SYNE1 gene. Another image depicts measuring the blood pressure in Syne1and Hmnc1 knockout mice.

Severe Acute Malnutrition (SAM)

Approximately two million children worldwide under the age of five experience severe malnutrition annually, with an estimated 20-30% not surviving. Classically, severe acute malnutrition (SAM) manifests in one of two forms: the non-edematous form (NESAM or marasmus) which is characterized by chronic wasting, and the edematous form (ESAM, kwashiorkor, or marasmic-kwashiorkor), characterized by more severe multisystem dysfunction. Despite decades of research, the underlying reasons why some children develop ESAM versus NESAM remain elusive, as the etiology of molecular differences in the pathophysiology underlying to two forms being largely unexplored. Our research employs a multi-'omics' approach, focusing on cohorts from diverse ancestries residing in regions where ESAM and SAM are prevalent [PMID: 31857576]. Within our laboratory, we are constructing a functional hepatocyte model to simulate fatty liver in ESAM cases, alongside identifying single nucleotide polymorphisms within ESAM and NESAM samples obtained from Jamaica and Malawi. Additionally, we are fostering international collaborations to establish a comprehensive repository of SAM samples, collaborating with researchers in SAM high-incidence countries to create a Kwashiorkor Collaborative Network (KwashNet). Through this we hope to better understand the etiologic and pathophysiologic differences between ESAM and NESAM. The findings of this study will be used to assist in the development of targeted interventions designed to correct the unique metabolic disturbances of kwashiorkor.

Figure depicts the process of using serum samples from children with malnutrition from Jamaica and Malawi and the discovery of dysregulated 1-carbon metabolite cycle and DNA hypomethylation in children with edematous severe acute malnutrition. On the right portion of the figure, it shows the flowchart of KwashNet, an international collaboration aimed to study the genetic etiology of severe acute malnutrition. Samples will be collected from a cohort and extracted DNA will be go through whole genome sequencing and analysis.

Sickle Cell Disease Alloimmunization

Sickle cell disease (SCD) is one of the most common monogenetic diseases in the world, with high mortality rates and a lowered life expectancy. Regular transfusion of red blood cells (RBCs) is a mainstay of treatment; however, repeated transfusions increase the risk of the recipent developing antibodies against donor RBCs (known as alloimmunization). RBC alloimmunization is seen in up to 20% of multiply-transfused SCD individuals, with some studies reporting rates twice as high. In the most severe cases, transfused patients develop alloantibodies with almost every new transfusion – so called transfusion ‘super-responders’; this creates a major challenge to find compatible blood for future transfusions. Fundamentally, the reason some individuals develop alloantibodies when most do not, remains unclear. In our previous studies, we identified a genome-wide significant association between an intergenic locus on chromosome 5q33 and being a transfusion responder and replicated this in a second cohort [PMID: 30578281]. We are utilizing a multiomics approach to fine map the functional consequence(s) of genetic variation our risk locus. We are also applying trans- and local-ancestry admixture mapping models to other cohorts of alloimmunization in sickle cell disease as a means of identifying novel risk alleles and refining the genetic risk for alloimmunization. Collectively, these efforts seek to provide insight to the immunological mechanisms underlying the increased alloimmunization risk, and in so doing, advance much needed therapeutic and diagnostic targets to improve the safety of this important clinical intervention.

Figure showing an individual with Sickle Cell Disease who may or may not develop alloantibodies after a blood transfusion. The lower portion of the image shows the pathway from recruitment of transfusion responders and non-responders to the development of a genetic risk assessment and clinical intervention.

Collaborative African Genomics Network (CAfGEN)

We are a part of a multi-national project funded by the NIH, Wellcome Trust, and African Academy of Sciences (AAS) known as the Human Health and Heredity in Africa (H3Africa) Consortium. The goals of the consortium are to establish and grow genomics and genetics technologies and expertise in Africa for the purposes of advancing human health and disease (www.h3africa.org; @H3Africa). Our project – the Collaborative African Genomics Network (CAfGEN; @CAfGEN1) is based in Botswana and includes clinical and/or research sites in Botswana, Uganda, eSwatini, and the United States. The main focus of the consortium is pediatric HIV/AIDS, which affects more than 1 million children in Africa under the age of 15 and imposes a significant health burden on affected countries. Collectively, the project seeks to use genetics and genomics to better understand the molecular drivers of the progression from HIV infection to AIDS and to improve the diagnosis of active tuberculosis disease in African children. These research aims also provide opportunities for training and development of genomics knowledge in the host countries. CAfGEN is using transcriptomics and genomics to describe the genetic ancestry and variation within African genomes and using the resulting information to refine the genes, pathways, and environmental influences involved in disease progression.

Publications

Mwesigwa S, Williams L, Retshabile G, Katagirya E, Mboowa G, Mlotshwa B, Kyobe S, Kateete DP, Wampande EM, Wayengera M, Mpoloka SW, Mirembe AN, Kasvosve I, Morapedi K, Kisitu GP, Kekitiinwa AR, Anabwani G, Joloba ML, Matovu E, Mulindwa J, Noyes H, Botha G; Collaborative African Genomics Network (CAfGEN); TrypanoGEN Research Group, Brown CW, Mardon G, Matshaba M, Hanchard NA. Unmapped exome reads implicate a role for Anelloviridae in childhood HIV-1 long-term non-progression. npj Genom Med. 2021 Mar 19;6(1):24. doi: 10.1038/s41525-021-00185-w.

Murdock DR, Dai H, Burrage LC, Rosenfeld JA, Ketkar S, Müller MF, Yépez VA, Gagneur J, Liu P, Chen S, Jain M, Zapata G, Bacino CA, Chao HT, Moretti P, Craigen WJ, Hanchard NA; Undiagnosed Diseases Network, Lee B. Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing. J Clin Invest. 2021 Jan 4;131(1):e141500. doi: 10.1172/JCI141500.

A Choudhury, S Aron, L Botigué, D Sengupta, G Botha, T Bensellak, G Wells, J Kumuthini, D Shriner, YJ Fakim, AW Ghoorah, E Dareng, T Odia, O Falola, E Adebiyi, S Hazelhurst, G Mazandu, OA Nyangiri, M Mbiyavanga, A Benkahla, SK Kassim, N Mulder, SN Adebamowo, ER Chimusa, RA Gibbs, D Muzny46, G Metcalf, TrypanoGEN Research Group‡, C Rotimi, M Ramsay, H3Africa Consortium‡, A Adeyemo, Z Lombard^, NA Hanchard^, High Depth African Genomes Inform Human Migration and Health. Nature. 2020 Oct;586(7831):741-748. doi: 10.1038/s41586-020-2859-7. Epub 2020 Oct 28.

KV Schulze, S Swaminathan, S Howell, A Jajoo, O Brown, R Sadat, N Hall, L Zhao, K Marshall, ME Reid, X Wang, JW Belmont, Y Guan, CA McKenzie, M Manary, I Trehan, NA Hanchard^. Edematous severe acute malnutrition is characterized by hypomethylation of DNA. Nat Comms. 2019 Dec 19;10(1):5791. doi: 10.1038/s41467-019-13433-6.

KV Schulze, A Bhatt, MS Azamian, N Sundgren, G Zapata, P Hernandez, K Fox, JR Kaiser, JW Belmont, NA Hanchard^. Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy. Genet in Med. 2019 Nov;21(11):2453-2461; PMID: 30992551

G Retshabile, B Mlotshwa, S Swaminathan, L Williams, S Mwesigwa, G Mboowa, A Kekitiinwa, M Joloba, F Yu, G Anabwani, SW Mpoloka, G Mardon, NA Hanchard^ for the Collaborative African Genomics Network of the H3Africa Consortium. Whole exome sequencing reveals uncaptured variation and distinct ancestry in the Southern African population of Botswana. Am J Hum Gen, 2018, May 3;102(5):731-743. PMID: 29706352; PMCID: PMC5986695

Sickle Cell Disease Ontology Working Group (NA Hanchard as co-author). The Sickle Cell Disease Ontology: Enabling universal sickle cell-based knowledge representation. Database (Oxford). 2019 Jan 1;2019:baz118; PMID: 31769834

L Williams, A Chen, J Moulds, Z Qi, S Hooker, S Campbell-Lee, R Kittles, Y Guan, NA Hanchard. A Genome-Wide Screen of RBC Alloimmunization Status in Sickle Cell Disease Reveals African-Ancestry-Limited Association at a locus on Chromosome 5. Blood Adv. 2018 Dec 26;2(24):3637-364; PMCID: PMC6306880

Mnika K, Mazandu GK, Jonas M, Pule GD, Chimusa ER, Hanchard NA, Wonkam A. Hydroxyurea-Induced miRNA Expression in Sickle Cell Disease Patients in Africa. Front Genet. 2019;10:509. doi: 10.3389/fgene.2019.00509. eCollection 2019. PubMed PMID: 31231425; PubMed Central PMCID: PMC6568309.

AH Li*, NA Hanchard*, M Azamian, S Fernbach, G Zapata, P Hernandez, DR Parekh, WJ Franklin, DJ Penny, CD Fraser, JR Lupski, RA Gibbs, E Boerwinkle, JW Belmont. Whole Exome Sequencing in 342 Left-Sided Lesion Cases Reveals Extensive Genetic Heterogeneity and Complex Inheritance Patterns Genome Med 2017 Oct 31;9(1):95. PMID: 29089047 PMCID: PMC5664429

Li AH, Hanchard NA, Azamian M, D'Alessandro LCA, Coban-Akdemir Z, Lopez KN, Hall NJ, Dickerson H, Nicosia A, Fernbach S, Boone PM, Gambin T, Karaca E, Gu S, Yuan B, Jhangiani SN, Doddapaneni H, Hu J, Dinh H, Jayaseelan J, Muzny D, Lalani S, Towbin J, Penny D, Fraser C, Martin J, Lupski JR, Gibbs RA, Boerwinkle E, Ware SM, Belmont JW. Genetic architecture of laterality defects revealed by whole exome sequencing. Eur J Hum Genet. 2019 Apr;27(4):563-573. doi: 10.1038/s41431-018-0307-z. Epub 2019 Jan 8. PubMed PMID: 30622330; PubMed Central PMCID: PMC6460585.

Hanchard NA, Swaminathan S, Bucasas K, Furthner D, Fernbach S, Azamian MS, Wang X, Lewin M, Towbin JA, D'Alessandro LC, Morris SA, Dreyer W, Denfield S, Ayres NA, Franklin WJ, Justino H, Lantin-Hermoso MR, Ocampo EC, Santos AB, Parekh D, Moodie D, Jeewa A, Lawrence E, Allen HD, Penny DJ, Fraser CD, Lupski JR, Popoola M, Wadhwa L, Brook JD, Bu'Lock FA, Bhattacharya S, Lalani SR, Zender GA, Fitzgerald-Butt SM, Bowman J, Corsmeier D, White P, Lecerf K, Zapata G, Hernandez P, Goodship JA, Garg V, Keavney BD, Leal SM, Cordell HJ, Belmont JW, McBride KL. A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20. Hum Mol Genet. 2016 Jun 1;25(11):2331-2341. doi: 10.1093/hmg/ddw071. Epub 2016 Mar 9. PubMed PMID: 26965164; PubMed Central PMCID: PMC5081047.