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Invited Commentary
Neurology
July 26, 2021

Finding a Place for Candidate Gene Studies in a Genome-Wide Association Study World

Author Affiliations
  • 1Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  • 2Henry and Allison McCance Center for Brain Health, Center for Genomic Medicine, Massachusetts General Hospital, Boston
  • 3Broad Institute of MIT and Harvard, Cambridge, Massachussetts
JAMA Netw Open. 2021;4(7):e2118594. doi:10.1001/jamanetworkopen.2021.18594

The best multivariable prognostic models account for approximately 35% of outcome variability in moderate to severe traumatic brain injury (TBI).1 Some residual outcome variability can be attributed to between-center differences. Better characterization of injury severity (eg, with advanced neuroimaging and blood biomarkers) is also likely to explain a large proportion of unexplained variability in outcome. However, even when accounting for these factors, it is likely that more than 50% of outcome variance remains unexplained. This suggests that patient-specific factors, not just injury severity, play important roles in modulating TBI outcomes.

Evidence of the association of patient genetics with TBI outcomes has been acquired in many ways. Rare but highly penetrant variants in genes, like CACNA1A (OMIM 601011), can cause life-threatening brain swelling in response to trivial head injury.2 While such high-impact variants are rare, the last few decades have been witness to multiple candidate gene association studies,3,4 which have investigated whether more common variants in a host of different genes might be associated with TBI outcomes. The choice of genetic variants in these studies has been driven by a priori hypotheses regarding TBI pathophysiology. While this approach is rational, candidate gene studies have recognized shortcomings,5 including low genetic coverage, selection bias, a high false positive rate, publication bias, and poor replication.

In contrast, genome-wide association studies (GWAS) examine genetic associations with disease phenotype (or, less commonly, outcome) across the whole genome. Their increasing use has provided important insights in many diseases, although not in TBI, to our knoweldge.5 GWAS are unbiased and data-driven, can address millions of common genetic variants, and have well-accepted thresholds for multiple comparison. While GWAS is generally applied to case-control samples, it can also be applied to quantitative traits in affected individuals. Given this background, it is legitimate to ask whether candidate gene studies, which restrict their assessment to individual genes or genome regions based on an a priori biological hypothesis, still have a role in understanding disease biology and supporting better practice.

The study by Jha et al6 provides an example of a candidate gene study with strong supporting evidence. The SUR1-TRPM4 channel complex, which includes the sulphonylurea receptor, has been implicated in the pathophysiological processes of contusion expansion in TBI. Therefore, Jha et al6 sought to determine whether genetic variations in 2 genes, ABCC8 (OMIM 600509) and TRPM4 (OMIM 606936), were associated with progression of intracerebral hemorrhage after severe TBI. Jha et al6 genotyped 40 variants in these genes in 321 patients with severe TBI from a single center (95 patients who underwent decompressive craniectomy were excluded). They found consistent signals that 4 upstream, relatively brain-specific single-nucleotide variations (SNVs; formerly single nucleotide polymorphisms) in ABCC8 were associated with increased risk of hemorrhage progression, and 4 SNVs in TRPM4 were associated with decreased hemorrhage progression. Addition of genetic information significantly improved estimation of hemorrhage progression compared with baseline models based on conventional clinical and laboratory covariates. Finally, Jha et al6 demonstrated (in silico) an association of the candidate SNVs with structure and function of the SUR1-TRPM4 channel.

These results are important for several reasons. They provide genetic support for a biological model that emerges from evidence in experimental models and clinical studies and add confidence to ongoing intervention studies of SUR1 antagonists in TBI. The findings by Jha et al6 may also allow us to assign risk of contusion expansion to individual patients, although replication would be essential before applying any such approach at the bedside. This could be clinically valuable, and ultimately allow selection of subpopulations of patients in whom this pathophysiological pathway has a greater role, thus enhancing the efficiency of clinical trials targeting the SUR1 receptor.

Although we must, as with all such candidate gene studies, proceed cautiously when there has not been independent replication, this study by Jha et al6 provides a template for how candidate gene studies, when coupled with meticulous dissection of associated biological processes, can still be relevant. The deep phenotyping in this analysis would have been difficult in the large sample sizes needed for GWAS, the strong biological priors provide confidence in the results beyond statistical significance, the results inform more sophisticated design and analysis of interventional trials, and, over time, the data provided could contribute to polygenic risk scores that help decision-making in individual patients.

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Article Information

Published: July 26, 2021. doi:10.1001/jamanetworkopen.2021.18594

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Menon DK et al. JAMA Network Open.

Corresponding Author: David K. Menon, MD, PhD, Division of Anaesthesia, Department of Medicine, University of Cambridge, PO Box 93, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom (dkm13@cam.ac.uk).

Conflict of Interest Disclosures: Dr Menon reported receiving grants from the European Union and UK National Institute for Health Research and personal fees from Lantmaanen, NeuroTrauma Sciences, Integra Neurosciences, Calico, GlaxoSmithKline, and PressuraNeuro outside of the submitted work. Dr Rosand reported receiving grants from National Institutes of Health and One Mind for Research during the conduct of the study and personal fees from Boehringer Ingelheim outside the submitted work.

References
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2.
Kors  EE, Terwindt  GM, Vermeulen  FL,  et al.  Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine.   Ann Neurol. 2001;49(6):753-760. doi:10.1002/ana.1031PubMedGoogle ScholarCrossref
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McFadyen  CA, Zeiler  FA, Newcombe  V,  et al.  Apolipoprotein E4 polymorphism and outcomes from traumatic brain injury: a living systematic review and meta-analysis.   J Neurotrauma. 2021;38(8):1124-1136. doi:10.1089/neu.2018.6052PubMedGoogle ScholarCrossref
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Zeiler  FA, McFadyen  C, Newcombe  VFJ,  et al.  Genetic influences on patient-oriented outcomes in traumatic brain injury: a living systematic review of non-apolipoprotein E single-nucleotide polymorphisms.   J Neurotrauma. 2021;38(8):1107-1123. doi:10.1089/neu.2017.5583PubMedGoogle ScholarCrossref
5.
Duncan  LE, Ostacher  M, Ballon  J.  How genome-wide association studies (GWAS) made traditional candidate gene studies obsolete.   Neuropsychopharmacology. 2019;44(9):1518-1523. doi:10.1038/s41386-019-0389-5PubMedGoogle ScholarCrossref
6.
Jha  RM, Zusman  BE, Puccio  AM,  et al.  Genetic variants associated with intraparenchymal hemorrhage progression after traumatic brain injury.   JAMA Netw Open. 2021;4(7):e2116839. doi:10.1001/jamanetworkopen.2021.16839Google Scholar
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