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Protective alleles and modifier variants in human health and disease

Nature Reviews Genetics volume 16, pages 689–701 (2015)Cite this article

Subjects

Key Points

  • Protective alleles confer protection against disease by disrupting protein function, typically via loss-of-function (LoF) effects.

  • Protective alleles have been identified for a range of complex disease phenotypes, such as Alzheimer disease and cardiometabolic disease, often within genes that contain known disease susceptibility variants.

  • Maintenance of health — and prevention of disease — are not attributable solely to individual protective alleles. Coding and non-coding regulatory regions of the genome (modifier variants) are likely to contribute to the overall genomic architecture of health, mimicking the situation with susceptibility to complex diseases.

  • Many protective alleles are low-frequency or rare alleles; studies that discovered these alleles have used large sample sizes across multi-ethnic cohorts, or specific founder populations in which individuals are more likely to harbour rare alleles and gene knockouts.

  • Discovery of LoF protective alleles has stimulated the development of drugs that mimic gene LoF or knockout effects for a range of phenotypes, with a successful example being the development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

  • The existence of protective LoF alleles and gene knockouts in otherwise healthy individuals suggests that drugs mimicking these LoF effects should demonstrate both efficacy and safety. However, evidence suggests that drug-induced gene knockout might not necessarily recapitulate the effects of LoF alleles.

Abstract

The combination of next-generation sequencing technologies and high-throughput genotyping platforms has revolutionized the pursuit of genetic variants that contribute towards disease. Furthermore, these technologies have provided invaluable insight into the genetic factors that prevent individuals from developing disease. Exploiting the evolutionary mechanisms that were designed by nature to help prevent disease is an attractive line of enquiry. Such efforts have the potential to generate a therapeutic target roadmap and rejuvenate the current drug-discovery pathway. By delineating the genomic factors that are protective against disease, there is potential to derive highly effective, genomically anchored medicines that assist in maintaining health.

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Figure 1: Population variation for common traits and how extreme phenotypes can provide unique insight into common disease biology.
Figure 2: Illustration of the close relationship between clinically relevant loss-of-function and gain-of-function alleles, using PCSK9 as an example.
Figure 3: Cis- and trans-acting modifier effects.

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Acknowledgements

Financial support was provided by the US National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) Clinical and Translational Science Award UL1TR0001114. A.R.H. was supported through the UK National Institute for Health Research Academic Foundation Programme.

Author information

Author notes

  1. Andrew R. Harper and Shalini Nayee: These authors contributed equally to this work.

Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford and Oxford University Hospitals NHS Foundation Trust, OX3 7BN, Oxford, UK

    Andrew R. Harper

  2. Department of Oral Medicine, Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK

    Shalini Nayee

  3. Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, 92037, California, USA

    Eric J. Topol

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Correspondence to Andrew R. Harper, Shalini Nayee or Eric J. Topol.

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Competing interests

E.J.T. consults for Illumina, Genapsys and Edico Genome and is a co-founder of Cypher Genomics. The other authors declare no competing interests.

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Glossary

Loss-of-function

(LoF). When an allele causes either partial or complete loss of gene expression. Complete loss of gene function is often termed a gene-knockout effect.

Next-generation sequencing

A high-throughput method of sequencing DNA, facilitating single-base-pair resolution across the entire genome.

Gain-of-function

(GoF). When an allele causes higher levels of gene expression than the 'normal' physiological level of gene expression.

Healthspan

The period of life during which an individual has optimal health, free from life-limiting disease.

Genome-editing techniques

Methods in which nucleases are used to induce specific variants within DNA, usually to bring about a phenotypic change (examples of techniques include CRISPR–Cas9 (clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9) and zinc-finger nucleases).

Monoclonal antibodies

Antibodies for a specific antigen made by identical immune cells cloned from a unique parent cell. Within pharmacology, monoclonal antibody-based drugs (denoted by the suffix -mab) are a form of biologic therapy that target specific antigen epitopes. These drugs were initially derived entirely from mouse antibodies, which resulted in high immunogenicity.

Humanized monoclonal antibody

A type of monoclonal antibody formed from mouse and human DNA sources. Humanized monoclonal antibody drugs consist primarily of human domains, with murine sequences being limited to the complementarity-determining region of the antibody, which results in lower immunogenicity than that associated with murine or chimeric monoclonal antibody drugs.

Variants with unknown significance

Variants for which there is insufficient information to determine whether the variant confers a benign or functional (pathogenic or protective) effect.

Allelic heterogeneity

The phenomenon in which multiple alleles within a locus confer the same phenotypic effect.

Founder populations

Populations that descend from a small number of 'founder' individuals, and therefore have reduced genetic diversity compared with outbred populations.

Haploinsufficiency

Where an individual has only one functional copy of a gene (rather than two functional copies), resulting in reduced levels of gene expression that alter the phenotype.

Transcription factor-binding site

A sequence of DNA that can be bound by transcription factors and thereby regulate transcription of coding regions of the genome.

Mosaicism

A term used to describe the occurrence of two or more cell populations that are derived from a single zygote but harbour different genotypes.

Morpholinos

Antisense oligonucleotides that are engineered to bind to specific mRNA sequences and inhibit protein synthesis, enabling researchers to determine the effects of reduced expression of the targeted gene.

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Harper, A., Nayee, S. & Topol, E. Protective alleles and modifier variants in human health and disease. Nat Rev Genet 16, 689–701 (2015). https://doi.org/10.1038/nrg4017

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