CDCV

Visscher PM, Brown MA, McCarthy MI & Yang J 2012 Five years of GWAS discovery. Am J Hum Genet 90:7-24.

• from McCLellan and King, Cell 2010¹:
• odds ratios of the magnitude generally detected by GWAS (<1.5) can frequently be explained by cryptic population stratification, regardless of the p value associated with them
• the common disease-common variant model has been the primary focus of human genomics over the last decade
• if common alleles influenced common diseases, many would have been found by now
• the issue is not how to develop still larger studies, or how to parse the data still further, but rather whether the common disease-common variant hypothesis has now been tested and found not to apply to most complex human diseases

• from Nicholas Wade in the New York Times, March 20 2011:
• about 2,000 sites on the human genome have been statistically linked with various diseases
• in many cases the sites are not inside working genes, suggesting there may be some conceptual flaw in the statistics
• it seemed that natural selection has weeded out any disease-causing mutation before it becomes common

• from a commentary article by Jonathan Latham, on guardian.co.uk, 17 April 2011:
• among all the genetic findings for common illnesses, such as heart disease, cancer and mental illnesses, only a handful are of genuine significance for human health
• faulty genes rarely cause, or even mildly predispose us, to disease
• as a consequence the science of human genetics is in deep crisis
• since the Collins paper [Manolio et al. 2009³] was published nothing has happened to change that conclusion
• the original twin-study critics were more right than they imagined
• the most likely explanation for why genes for common diseases have not been found is that, with few exceptions, they do not exist

• there are now well over 2000 loci that are significantly and robustly associated with one or more complex traits
• the vast majority of the loci identified are new
• before 2007 their association with disease or other complex traits was not known

• at this point in time, we can conclude that
• many loci contribute to complex-trait variation
• at a number of identified risk loci, there are multiple alleles associated with disease at a wide range of frequencies.
• there is evidence for pleiotropy
• a number of variants associated with disease or complex traits in one ethnic population are also associated the same disease or traits in other populations
• the hypothesis⁷⁶ that causal variant(s) that lead to the association between common SNPs and disease are mostly rare (say, have an allele frequency of 1% or lower) is not consistent with theoretical and empirical results
• there is no widespread evidence for the existence of "synthetic associations"
• a surprisingly large proportion of additive genetic variation is tagged when all SNPs are considered simultaneously

• (1) is the GWAS approach founded on a flawed assumption that genetics plays an important role in the risk for common diseases?
• the proportion of total variation explained by genome-wide-significant variants has reached 10%–20% for a number of diseases
• clearly there are additional variants with such small effect sizes that they have not been detected with stringent significance
• many of the detected loci are in biologically meaningful pathways
• whole-genome analyses involving GWAS data have estimated that 20%–50% of phenotypic variation is captured when all SNPs are considered simultaneously for a number of complex diseases and traits
• these estimates are based on population-wide studies and provide a lower limit of the total proportion of phenotypic variation due to genetic factors
• these studies have provided independent evidence for the role of genetics in common diseases

• (2) have GWASs been disappointing in not explaining more genetic variation in the population?
• this criticism implies that the aim of GWASs is to explain all genetic variation
• this is a misrepresentation of the objective of GWASs
• for a number of complex traits the proportion of genetic variation uncovered by GWASs is actually substantial
• for T2D, MS, and CD, approximately 10%, 20%, and 20%, respectively, of genetic variation in the population has been accounted for
• apart from diseases with a known major locus (which is usually the major histocompatibility locus), the baseline of variation explained five years ago was essentially zero

• (3) have GWASs delivered meaningful biologically relevant knowledge or results of clinical or any other utility?
• the answer to this question is a definite "yes"
• there have been few, if any, similar bursts of discovery in the history of medical research

• (4) are GWAS results spurious?
• the combination of large sample sizes and stringent significance testing has led to a large number of robust and replicable associations between complex traits and genetic variants, many of which are in meaningful biological pathways