Common and rare variants in multifactorial susceptibility to common diseases

By W. Bodmer, C. Bonilla. Nature Genetics, 2008

1,153 citations recorded by the source corpus.

Here, we give a historical overview of the search for genetic variants that influence the susceptibility of an individual to a chronic disease, from RA Fisher's seminal work to the current excitement of whole-genome association studies (WGAS). We then discuss the concepts behind the identification of common variants as disease causal factors and contrast them to the basic ideas that underlie the rare variant hypothesis. The identification of rare variants involves the careful selection of candidate genes to examine, the availability of highly efficient resequencing techniques and the appropriate assessment of the functional consequences of the implicated variant. We believe that this strategy can be successfully applied at present in order to unravel the contribution of rare variants to the multifactorial inheritance of common diseases, which could lead to the implementation of much needed preventative screening schemes.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/c61bf7414278ad46459990f68100375ae4639bdb

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

Citations in the corpus

The advantages and limitations of trait analysis with GWAS: a review (2013, background): “The situation looks different in humans, where typically a large number of small effect loci are found and most analyses require several thousand individuals to detect these [32,33].”
Genome-wide association analysis of metabolic traits in a birth cohort from a founder population (2008, background): “Such rare variants could have substantial effects in small numbers of individuals and, in aggregate, represent a substantial proportion of trait variance in the populatio”
A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic (2009, background): “Recent studies support the hypothesis that multiple rare mutations, each with a low marginal effect, may be a major player in genetic determination of susceptibility for some complex diseases [3–13].”
Genome-wide association studies in diverse populations (2010, background): “Rare variants, which have not been examined to the same extent, provide one possible genetic source for unexplained phenotypic variatio”
Human genetic variation and its contribution to complex traits (2009, background): “The opposing theory, the rare variant hypothesis, posits that common complex traits are the summation of low-frequency, high-penetrance variant”
Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. (2012, background): “, π̂n) is a vector of the estimated probability of y under the null model (3), and K = GWWG′ is an n × n kernel matrix, where G = (G1, .”
Imputing Amino Acid Polymorphisms in Human Leukocyte Antigens (2013, background): “In many instances, the observed HLA effects dwarf those of other associated variants throughout the rest of the genome [6].”
Fine-mapping from summary data with the “Sum of Single Effects” model (2021, result): “This was intended to mimic the typical situation encountered in genome-wide association studies [45, 46].”
Selecting causal genes from genome-wide association studies via functionally-coherent subnetworks (2014, neutral): “Cognition Cognitive performance (1) 1 57 5.”
The diagnosis of mental disorders: the problem of reification. (2010, background): “2008, Morrow et al. 2008, T. Walsh et al. 2008, Weiss et al. 2008, Xu et al. 2008), perhaps acting against a risk-laden genetic background produced by common variants (Bodmer & Bonilla 2008).”
Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics (2011, background): “An alternative, the common disease/rare variant (CDRV) hypothesis, posits that many genes/alleles with lower-frequency, higher-penetrance variants contribute to disease and is a straightforward extension to common diseases of the discoveries made for Mendelian disorders (Bodmer and Bonilla 2008).”
Missing heritability and strategies for finding the underlying causes of complex disease (2010, background): “These variants, although individually rare, are collectively frequent, and even though their effect sizes are greater than those observed for common variants, they are not large enough to produce familial aggregatio”