Are rare variants responsible for susceptibility to complex diseases?

By J. K. Pritchard. American Journal of Human Genetics, 2001

1,255 citations recorded by the source corpus.

View Paper: https://www.semanticscholar.org/paper/4b5095f53f10f0fb29ea6fbe57ea61f84450b677

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

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics (2011, background): “Therefore, Pritchard (2001) argued that the CDRV hypothesis is more consistent with human pathology and population biology than the CDCV hypothesis.”
Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. (2003, background): “This is consistent with a genetic model of complex disease in which mildly deleterious mutations may have quite high allele frequencies (40).”
Prediction of individual genetic risk to disease from genome-wide association studies. (2007, background): “…distribution of allele frequencies that broadly corresponds to the common-disease common-variant (CDCV) hypothesis (Chakravarti 1999; Reich and Lander 2001), in which the frequency of the increasing risk allele was simulated as pi ∼ Uniform(0.01,0.99), or a U-shaped distribution that broadly…”
Linear Hypothesis Testing in Dense High-Dimensional Linear Models (2016, background): “However, there is little reason to believe that the sparsity of β ∗ needs to hold in practice (Hall et al., 2014; Ward, 2009; Jin and Ke, 2014; Pritchard, 2001).”
PLINK: a tool set for whole-genome association and population-based linkage analyses. (2007, background): “Under this model, the considerable levels of heritability could reflect aggregates of very many, very rare variants (each potentially of moderate effect but accounting for virtually none of the variation at the population level), which we refer to as the “multiple rare variant” (MRV) hypothesis.(13)”
A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic (2009, background): “As discussed in [32], a human gene may contain up to 1000 disease susceptibility variants, whereof only a part are polymorphic in a given sample.”
Common vs. Rare Allele Hypotheses for Complex Diseases (2009, positive): “For example, Pritchard [6], argued that population processes operative in the human lineage would be more likely to favor the existence of multiple rare variations contributing to disease rather than common variations.”
The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease (2007, methodology): “We collected these data sets with restricted ancestral origins in order to minimize the confounding effects of allelic heterogeneit”
Rare independent mutations in renal salt handling genes contribute to blood pressure variation (2008, background): “, raising the possibility that rare independent variants account for a large fraction of blood pressure variation, as would be expected if trait alleles are under purifying selectio”
The evolutionary genetics of personality (2007, background): “…the total number of genetic loci that could potentially affect the trait if they became polymorphic due to mutation, not the number of loci that are actually polymorphic at a given point in time (i.e. the QTLs), which are only about 10% of the potential loci (Pritchard, 2001; Rudan et al., 2003).”
Genome-wide association studies: theoretical and practical concerns (2005, methodology): “Arguments used to support these two hypotheses have largely been based on population-genetic theories and will therefore be influenced by the underlying assumptions of these theorie”
Patterns of linkage disequilibrium in the human genome (2002, background): “It is also worth briefly noting that the use of LD for mapping relies on assumptions regarding the genetic architecture of common diseases that are open to question; this point is discussed extensively elsewher”
Uncovering the roles of rare variants in common disease through whole-genome sequencing (2010, background): “Taken together, these observations support the long-established idea that rare variants could be the primary drivers of common disease”
The allelic architecture of human disease genes: common disease-common variant...or not? (2002, methodology): “For loci with the highest mutation rates, Pritchard noted that ‘it is unlikely that any single mutation will constitute a large fraction of the susceptible class.”