Rare and common variants: twenty arguments

In the paper

“As of June 2011, the NHGRI GWAS catalog lists 1,449 genome-wide significant associations with 237 traits and diseases, spread across all chromosome except the Y99.”

What the sources say

• Not checked yetcites [99] Manolio, T. A., Brooks, L. D. & Collins, F. S. A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590–1605 (2008). source

In the paper

“In all likelihood, each of the three genetic architectures contributes, possibly to different degrees, to different diseases or traits.”

In the paper

“There are two major obstacles to detecting epistasis: very large samples are required to find sufficient individuals of each genotype combination to accurately measure small effects, and the number of comparisons scales exponentially with the number of interactions so the testing burden is enormous.”

In the paper

“The argument has been made that relaxed selection in modern humans may favor the accumulation of deleterious rare alleles, greatly increasing the prevalence of disease hundreds of generations into the future30.”

What the sources say

• Not checked yetcites [30] Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl Acad. Sci. USA 107, 961–968 (2010). source

In the paper

“One of the difficulties may be that the environment is difficult to define and measure, and it may be unique individual exposures that are more important than exposures shared by thousands of people.”

In the paper

“Similarly, there is as yet little evidence for environmental modification of genotype effects: a recent example relating to the protective effect of coffee consumption and Parkinson’s disease risk provides an exception108.”

What the sources say

• Not checked yetcites [108] Hamza, T. H. et al. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLoS Genet. 7, e1002237 (2011). source

In the paper

“Genome-wide association studies (GWAS) are not generally powered to detect epistasis or G×E121, and they are not designed to detect epigenetic influences122”

What the sources say

• Not checked yetcites [121] Bhattacharjee, S. et al. Using principal components of genetic variation for robust and powerful detection of gene-gene interactions in case–control and case-only studies. Am. J. Hum. Genet. 86, 331–342 (2010). source
• Not checked yetcites [122] Slatkin, M. Epigenetic inheritance and the missing heritability problem. Genetics 182, 845–850 (2009). source

In the paper

“The notion is that a disease such as schizophrenia is actually a collection of hundreds, or possibly even thousands, of similar conditions attributable to rare variants at individual loci18.”

What the sources say

• Not checked yetcites [18] McClellan, J. M., Susser, E. & King, M.-C. Schizophrenia: a common disease caused by multiple rare alleles. Br. J. Psychiatry 190, 194–199 (2007). source

In the paper

“Synthetic genetic interaction screens in yeast123,124 have demonstrated that thousands of combinations of individually viable mutations can jointly be lethal, and similar examples have been documented in Drosophila melanogaster and Caenorhabditis elegans125,126.”

What the sources say

• Not checked yetcites [123] Tong, A. H. et al. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294, 2364–2368 (2001). source
• Not checked yetcites [124] Costanzo, M. et al. The genetic landscape of a cell. Science 327, 425–431 (2010). source
• Not checked yetcites [125] Lucchesi, J. C. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanogaster. Genetics 59, 37–44 (1968). source
• Not checked yetcites [126] Lehner, B. et al. Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling program. Nature Genet. 38, 896–903 (2006). source

In the paper

“Since disease is deleterious to fitness, variants that promote disease should be selected against, and hence disease-promoting variants should not be common3,26,27.”

What the sources say

• Not checked yetcites [3] Pritchard, J. K. & Cox, N. J. The allelic architecture of human disease genes: common disease–common variant... or not? Hum. Mol. Genet. 11, 2417–2423 (2002). source
• Not checked yetcites [26] Bulmer, M. G. The effect of selection on genetic variability. Am. Nat. 105, 201–211 (1971). source
• Not checked yetcites [27] Barton, N. H. & Turelli, M. Evolutionary quantitative genetics: how little do we know? Annu. Rev. Genet. 23, 337–370 (1989). source

In the paper

“It has been appreciated for some time that the distribution of minor allele frequencies (MAFs) is strongly skewed towards an excess of rare variants: over a third of all polymorphisms have frequencies below 5%31.”

What the sources say

• Not checked yetcites [31] Hartl, D. L. & Clark, A. G. Principles of Population Genetics 3rd edn (Sinauer Associates, Sunderland, USA, 1998).

In the paper

“Here it simply signifies the idea that the heritability is not so much missing, as hidden beneath the significance thresholds used to define risk alleles with high confidence15.”

What the sources say

• Not checked yetcites [15] Gibson, G. Hints of hidden heritability in GWAS. Nature Genet. 42, 558–560 (2010). source

In the paper

“Ultimately, every gene contributes to every trait, but with effect sizes so small that it would take samples greater than the population size of the species to detect them.”

In the paper

“since GWAS only measure the average effects of alleles across thousands of individuals, they are incapable of capturing heterogeneity of effect sizes at the family level that would be the hallmark of these broader components of the genetic architecture.”

In the paper

“Mutation rates are sufficiently large that purifying selection cannot remove all deleterious variants, and those that have a modest effect on fitness (for example, if they influence late-onset diseases 29) may rise to allele frequencies of 1% or occasionally more, particularly if the effect is recessive.”

What the sources say

• Not checked yetcites [29] Charlesworth, B. Fisher, Medawar, Hamilton and the evolution of aging. Genetics 156, 927–931 (2000). source

In the paper

“Additionally, epistatic effects are generally thought to be likely to be small relative to main effects, and the GWAS literature provides few examples of departure from additivity.”

In the paper

“For a disease with a high heritability of 80%, theory indicates that the number of contributing loci can range from over 500 with GRR of just 2 and one very rare variant per locus, to just a dozen loci with GRR of 5 and allele frequencies of 1% or if the disease is relatively common19.”

What the sources say

• Not checked yetcites [19] Wray, N. R., Purcell, S. M. & Visscher, P. M. Synthetic associations created by rare variants do not explain most GWAS results. PLoS Biol. 9, e1000579 (2011). source

In the paper

“It need not follow that the reduction in fitness is due to promotion of chronic disease, and the observation does not equate to saying that all rare non-synonymous variants are deleterious.”

In the paper

“GWAS are neither powered nor designed to detect variation under any of these models on a consistent basis, so there is as yet insufficient empirical data to resolve the debate.”

In the paper

“as shown by the massive meta-analyses of GWAS for height and body mass index (BMI)13,14, each involving several hundred thousand people, it is unlikely that more than a few hundred loci will ever be confirmed for most diseases, and these will not necessarily explain even half of the genetic variance.”

What the sources say

• Not checked yetcites [13] Speliotes, E. K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genet. 42, 937–948 (2010). The largest GWAS meta-analysis to date shows that hundreds of complex variants influence continuous traits. source
• Not checked yetcites [14] Lango-Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010). source

In the paper

“It is thus incontrovertible that rare variants contribute to disease risk, and that identification of such alleles is a powerful mode of genetic analysis.”

In the paper

“Nevertheless, the rare allele model must not only explain association data in populations, but also fit demographic distributions of disease within and among families, and there is little theory supporting the claim that they can do both55–57.”

What the sources say

• Not checked yetcites [55] Risch, N. Linkage strategies for genetically complex traits: I. Multilocus models. Am. J. Hum. Genet. 46, 222–228 (1990).
• Not checked yetcites [56] Slatkin, M. Genotype-specific risks as indicators of the genetic architecture of complex diseases. Am. J. Hum. Genet. 83, 120–126 (2008). source
• Not checked yetcites [57] Hemminki, K. & Bermejo, J. L. The 'common disease–common variant' hypothesis and familial risks. PLoS ONE 3, e2504 (2011). source

In the paper

“the consistent observation is that all diseases have significant heritability, and hence purifying selection has been unable to purge the population of disease-promoting variants2.”

What the sources say

• Not checked yetcites [2] Reich, D. E. & Lander, E. S. On the allelic spectrum of human disease. Trends Genet. 17, 502–510 (2001). source

In the paper

“Paternal age effects on psychological disease63 might be attributed to elevated mutation rates in sperm, but other hypotheses are equally compatible with the data, and maternal age effects operate in the opposite direction as younger mothers have higher likelihoods of having affected children64.”

What the sources say

• Not checked yetcites [63] Malaspina, D. et al. Advancing paternal age and the risk of schizophrenia. Arch. Gen. Psychiatry 58, 361–367 (2001). source
• Not checked yetcites [64] Lopez-Castroman, J. et al. Differences in maternal and paternal age between schizophrenia and other psychiatric disorders. Schizophr. Res. 116, 184–190 (2010). source

In the paper

“If rare variants are recently derived relative to the common variants, then they should be at different frequencies in Caucasians and Asians, and we would expect that they would only induce synthetic common variant associations in one of these populations, or at least would not tend to have the same magnitude of effect.”

In the paper

“diabetes and heart disease have greatly increased in incidence in India and China in the past 10 years60,61, an epidemiological transition that at best implies a change in penetrance of genetic effects attributable to any class of variant, rare or common, in the contemporary environment.”

What the sources say

• Not checked yetcites [60] Amutha, A. et al. Clinical profile of diabetes in the young seen between 1992 and 2009 at a specialist diabetes centre in south India. Prim. Care Diabetes 5, 223–229 (2011). source
• Not checked yetcites [61] Chan, J. C. et al. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 301, 2129–2140 (2009). source

In the paper

“At face value, the existence of dozens of susceptibility alleles for metabolic and immunological diseases with effect sizes that are just not detected for psychological diseases implies a difference in genetic architecture between the two categories of conditions.”

In the paper

“Compound heterozygosity for two different rare variants at one locus is well documented in diseases such as cystic fibrosis, hemochromatosis and sickle cell syndromes”

In the paper

“well-known examples include rare variants promoting atherosclerosis through hypercholesterolemia39, the lesions responsible for Maturity Onset Diabetes of the Young (MODY)40, and the BRCA1 and BRCA2 breast cancer susceptibility mutations41.”

What the sources say

• Not checked yetcites [39] Goldstein, J. L. & Brown, M. S. The LDL receptor locus and the genetics of familial hypercholesterolemia. Annu. Rev. Genet. 13, 259–289 (1979). source
• Not checked yetcites [40] Weedon, M. N. & Frayling, T. M. Insights on pathogenesis of type 2 diabetes from MODY genetics. Curr. Diab. Rep. 7, 131–138 (2007). source
• Not checked yetcites [41] Easton, D. F. et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am. J. Hum. Genet. 81, 873–883 (2007). source

In the paper

“On the face of it, the widely documented additivity of genetic associations is inconsistent either with the dominance of rare variant effects, or the assumption that they interact multiplicatively within individuals to influence disease.”

In the paper

“extension of the concept to include intergenic multiple heterozygosity could represent a large source of genetic variance that is almost impossible to detect with current methods.”

In the paper

“Nevertheless, the simplest interpretation of the consistency of common variant effects is that they are actually due to the common variants themselves or to unobserved common variants in high LD across all populations.”

In the paper

“These effects are less highly penetrant than Mendelian mutations, implying modification by the genetic background.”

In the paper

“Since the majority of the genetic variance remains unexplained, it is a priori just as likely to exist in the form of rare or common alleles, and the fact is that there is nothing about GWAS findings that is inconsistent with the infinitesimal model of many variants of very small effect across the full allele frequency spectrum.”

In the paper

“Under a mutation-selection balance model, it may be possible for different novel rare variants to have effects in each population, and fine mapping studies sometimes reveal subtle differences in the patterns of association [eg.67,68.”

What the sources say

• Not checked yetcites [67] Sim, X. et al. Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia. PLoS Genet. 7, e1001363 (2011). source
• Not checked yetcites [68] Waters, K. M. et al. Generalizability of associations from prostate cancer genome-wide association studies in multiple populations. Cancer Epidemiol. Biomarkers Rev. 18, 1285–1289 (2009). source

In the paper

“This may imply different intensities of purifying selection, although other models, including decanalization69, are also compatible with the data.”

What the sources say

• Not checked yetcites [69] Gibson, G. Decanalization and the origins of complex disease. Nature Rev. Genet. 10, 134–140 (2009). source

In the paper

“In the case of the ciliopathies, there is evidence from functional assays that rare variants can both promote and modify the severity of disease49.”

What the sources say

• Not checked yetcites [49] Davis, E. E. et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nature Genet. 43, 189–196 (2011). source

In the paper

“Schizophrenia, a disease with very high heritability (inferred from twin studies) and for which very few replicated GWAS hits have been identified despite extensive scans, nevertheless shows such demographic influences as whether the parents live in rural or urban areas (disease rates are elevated in children born after migration to cities)62.”

What the sources say

• Not checked yetcites [62] Saha, S., Chant, D., Welham, J. & McGrath, J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2, e141 (2005). source

In the paper

“Under multiplicative models, disease may cluster in families due to segregation of multiple rare variants that happen to be brought together in the pedigree.”

In the paper

“analyses of the distribution of risk allele frequencies across 8 traits argues that if anything minor allele frequencies are skewed to be greater than 0.2, providing strong empirical evidence that rare alleles are not alone responsible53.”

What the sources say

• Not checked yetcites [53] Park, J.-H. et al. Distribution of allele frequencies and effect sizes and their inter-relationships for common genetic susceptibility variants. Proc. Natl Acad. Sci. USA 108, 18026–18031 (2011). source

In the paper

“No-one doubts that some fraction of the total risk for any complex disease is due to rare alleles, but these studies argue that it is not the majority.”

What the sources say

• Not checked yetcites [53] Park, J.-H. et al. Distribution of allele frequencies and effect sizes and their inter-relationships for common genetic susceptibility variants. Proc. Natl Acad. Sci. USA 108, 18026–18031 (2011). source

In the paper

“Rare variants, particularly those at a frequency of less than 1%, need to be sequenced directly.”

In the paper

“Although association tests are reasonably powered to detect common variants that have a genotypic relative risk of 1.2 or more in meta-analyses that include tens of thousands of individuals, detecting the effects of single rare variant remains problematic.”

In the paper

“It is of course possible that disease represents a discrete phase shift (in gene expression profiles, for example) that takes the organism outside the normal range of continuous variation.”

In the paper

“Variance is distributed along all of the chromosomes, and is therefore attributable to hundreds of loci.”

In the paper

“of the cheek bones, or curve of the lips, run strongly in families, appearing in distant relatives in patterns that are suggestive of large genetic effects.”

What the sources say

• Not checked yetcites [105] Jelenkovic, A., Poveda, A,, Susanne, C. & Rebato, E. Contribution of genetics and environment to craniofacial anthropometric phenotypes in Belgian nuclear families. Hum. Biol. 80, 637–654 (2008). source

In the paper

“and it is not obvious that the normal variability is relevant to pathology.”

In the paper

“In several instances where SNP-wise GWAS has uncovered few loci, this approach has provided clear evidence for polygenic risk, but it must be recognized that the high variance in estimation of effects results in noisy scores that, although highly significant in the replication sample, only capture over an order of magnitude less of the variance and are far from predictive.”

What the sources say

• Not checked yetcites [53] Park, J.-H. et al. Distribution of allele frequencies and effect sizes and their inter-relationships for common genetic susceptibility variants. Proc. Natl Acad. Sci. USA 108, 18026–18031 (2011). source

In the paper

“A more pointed argument against the infinitesimal nature of effects is that it predicts less granularity in the distribution of risk and phenotypic trait variation than is often observed, though I am not aware of a quantitative assessment of this claim.”

In the paper

“A technical argument against all common variant models is that association alone is insufficient evidence of function: correlation is not causation.”

In the paper

“Since common variants are used for the partitioning it is most parsimonious to conclude that they are responsible, and simulations of rare variants so distributed capture much less of the variance.”

In the paper

“(ii) increasing burden of complex disease in the span of one or two generations (both of these phenomena are obvious upon browsing the CDC website at http://www/cdc/gov for incidence data)”

In the paper

“Furthermore, homophily, the tendency for couples to pair on the basis of shared attributes (including sub-clinical disease indicators), will tend to enrich for variants that promote those attributes104.”

What the sources say

• Not checked yetcites [104] Fowler, J. H, Settle, J. E. & Christakis, N. A. Correlated genotypes in friendship networks. Proc. Natl Acad. Sci. USA 108, 1993–1997 (2011). source

In the paper

“It is little appreciated that GWAS do not actually measure heritability (the ratio of genetic to total phenotypic variance in a population) but rather they measure just the genetic variance.”

In the paper

“Some of these may be due to LD with rare variants, but parsimony suggests most are common variant effects.”

In the paper

“On this model, the rare variant can either increase or decrease function, and whether or not it associates with disease will be conditional on the background liability.”

In the paper

“In these cases, it can be argued that the infinitesimal model does not capture the full range of genetic variance, and that there is a true missing heritability problem that will need to be addressed with rare alleles and broad sense heritability components that were introduced in Box 1.”

In the paper

“Disease arises either in individuals at the extremes of the liability scale who move beyond the threshold, or in individuals close to the threshold who are pushed into adversity through environmental and behavioral agents, or because they carry one or more rare variants.”