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Veterinary journal (London, England : 1997)2014; 202(3); 543-549; doi: 10.1016/j.tvjl.2014.09.013

Risk of false positive genetic associations in complex traits with underlying population structure: a case study.

Abstract: Genome-wide association (GWA) studies are widely used to investigate the genetic etiology of diseases in domestic animals. In the horse, GWA studies using 40-50,000 single nucleotide polymorphisms (SNPs) in sample sizes of 30-40 individuals, consisting of only 6-14 affected horses, have led to the discovery of genetic mutations for simple monogenic traits. Equine neuroaxonal dystrophy is a common inherited neurological disorder characterized by symmetric ataxia. A case-control GWA study was performed using genotypes from 42,819 SNP marker loci distributed across the genome in 99 clinically phenotyped Quarter horses (37 affected, 62 unaffected). A significant GWA was not achieved although a suggestive association was uncovered when only the most stringently phenotyped NAD-affected horses (n = 10) were included (chromosome 8:62130605 and 62134644 [log(1/P) = 5.56]). Candidate genes (PIK3C3, RIT2, and SYT4) within the associated region were excluded through sequencing, association testing of uncovered variants and quantitative RT-PCR. It was concluded that variants in PIK3C3, RIT2, and SYT4 are not responsible for equine neuroaxonal dystrophy. This study demonstrates the risk of false positive associations when performing GWA studies on complex traits and underlying population structure when using 40-50,000 SNP markers and small sample size.
Published by Elsevier Ltd.
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Publication Date: 2014-09-21 PubMed ID: 25278384PubMed Central: PMC4337777DOI: 10.1016/j.tvjl.2014.09.013Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study investigated the risk of inaccuracies in genetic association studies, particularly the chances of ‘false positives’ when studying complex traits in populations, using the example of equine neuroaxonal dystrophy (a neurological disorder in horses). Despite initial suggestive associations, the research concluded that specific gene variants weren’t actually responsible for the disorder, highlighting the need for caution when interpreting similar study results.

Overview of the research

  • The research discusses the implications and risks related to Genetic-Wide Association (GWA) studies, which are widely used to study genetic causes of diseases in domestic animals, particularly horses in this case. The concern with these studies is around the risk of ‘false positives’ i.e., erroneously identifying a correlation or a cause-and-effect relationship between certain genes and diseases.
  • The study used single nucleotide polymorphisms (SNPs) which are variations at a single position in a DNA sequence among individuals. Typically, 40-50,000 SNPs were studied in a sample size of 30-40 horses, including 6-14 horses affected by the disease.

Focused Area: Equine Neuroaxonal Dystrophy

  • Specifically, the study was centered around Equine neuroaxonal dystrophy (NAD), a common inherited neurological disorder in horses characterized by symmetric ataxia (lack of voluntary coordination of muscle movements).
  • A case-control GWA study was carried out using genetic data from 42,819 SNP marker loci across the genome in 99 Quarter Horses. Despite initial findings, a significant GWA was not achieved.

Speculative Genetic Causes and Conclusions

  • A suggestive association was found when only the most carefully phenotyped NAD-affected horses were included, particularly on a single chromosome site. The study elaborates further by identifying three candidate genes (PIK3C3, RIT2, and SYT4) within the associated region that were initially implicated.
  • However, after further sequencing and testing of these identified variants along with quantitative RT-PCR (a technique to measure the amount of a specific RNA), it was concluded that variants in these three genes are not responsible for equine neuroaxonal dystrophy. This led to the realization that the initial discovery was likely a false positive.
  • In concluding, the study underlines the risk involved with GWA studies when dealing with complex traits in population structures, emphasizing the heightened possibility of fallacious links when using 40-50,000 SNP markers and a small sample size.

Cite This Article

APA
Finno CJ, Aleman M, Higgins RJ, Madigan JE, Bannasch DL. (2014). Risk of false positive genetic associations in complex traits with underlying population structure: a case study. Vet J, 202(3), 543-549. https://doi.org/10.1016/j.tvjl.2014.09.013

Publication

Veterinary journal (London, England : 1997)
ISSN: 1532-2971
NlmUniqueID: 9706281
Country: England
Language: English
Volume: 202
Issue: 3
Pages: 543-549
PII: S1090-0233(14)00382-7

Researcher Affiliations

Finno, Carrie J
  • Department of Population Health and Reproduction, University of California, Davis, CA 95616, USA. Electronic address: cjfinno@ucdavis.edu.
Aleman, Monica
  • Department of Medicine and Epidemiology, University of California, Davis, CA 95616, USA.
Higgins, Robert J
  • Department of Pathology, Microbiology and Immunology, University of California, Davis, CA 95616, USA.
Madigan, John E
  • Department of Medicine and Epidemiology, University of California, Davis, CA 95616, USA.
Bannasch, Danika L
  • Department of Population Health and Reproduction, University of California, Davis, CA 95616, USA.

MeSH Terms

  • Animals
  • Female
  • Genome-Wide Association Study / veterinary
  • Genotype
  • Horse Diseases / genetics
  • Horses
  • Male
  • Neuroaxonal Dystrophies / genetics
  • Neuroaxonal Dystrophies / veterinary
  • Polymorphism, Single Nucleotide
  • Risk

Grant Funding

  • K01 OD015134 / NIH HHS
  • L40 TR001136 / NCATS NIH HHS
  • T32 DC008072 / NIDCD NIH HHS
  • 5 T32DC 8072-3 / NIDCD NIH HHS

Conflict of Interest Statement

None of the authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper.

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