Part of the perception problem is that some biologists had anticipated that many conditions (phenotypes or disease susceptibility factors) would be controlled by small numbers of (Mendelian) genes. In my opinion, anyone with a decent understanding of complexity would have found this prior highly implausible. (There is another possibility for why some researchers pushed the Mendelian scenario: drug discovery and big, rapid breakthroughs are more likely under that assumption.) In any case, what has been discovered is what I anticipated: many genes, each of small effect, control each phenotype. This is no reason for despair (well, perhaps it is if your main interest is drug discovery) -- incredible science is right around the corner as costs decrease and sample sizes continue to grow. Luckily, much of the genetic variance is linear, or additive, so can be understood using relatively simple mathematics.
In the figure, note that there were no hits (SNP associations) for height until sample size of close to 20,000 individuals (but progress has been rapid as sample sizes continue to grow). We are only now approaching this level of statistical power for IQ.
... The Cost of GWASs: If we assume that the GWAS results from Figure 1 represent a total of 500,000 SNP chips and that on average a chip costs $500, then this is a total investment of $250 million. If there are a total of ~2,000 loci detected across all traits, then this implies an investment of $125,000 per discovered locus. Is that a good investment? We think so: The total amount of money spent on candidate-gene studies and linkage analyses in the 1990s and 2000s probably exceeds $250M, and they in total have had little to show for it. Also, it is worthwhile to put these amounts in context. $250M is of the order of the cost of a one-two stealth fighter jets and much less than the cost of a single navy submarine. It is a fraction of the ~$9 billion cost of the Large Hadron Collider. It would also pay for about 100 R01 grants. Would those 100 non-funded R01 grants have made breakthrough discoveries in biology and medicine? We simply can’t answer this question, but we can conclude that a tremendous number of genuinely new discoveries have been made in a period of only five years.
... 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. A number of variants or different variants at the same loci have been shown to be associated with the same trait in different ethnic populations, and some loci are even replicated across species.81 The combination of multiple variants with small effect sizes has been shown to predict disease status or phenotype in independent samples from the same population. Clearly, these results are not consistent with flawed inferences from GWASs.
... In conclusion, in a period of less than five years, the GWAS experimental design in human populations has led to new discoveries about genes and pathways involved in common diseases and other complex traits, has provided a wealth of new biological insights, has led to discoveries with direct clinical utility, and has facilitated basic research in human genetics and genomics. For the future, technological advances enabling the sequencing of entire genomes in large samples at affordable prices is likely to generate additional genes, pathways, and biological insights, as well as to identify causal mutations.
What was once science fiction will soon be reality.
Long ago I sketched out a science fiction story involving two Junior Fellows, one a bioengineer (a former physicist, building the next generation of sequencing machines) and the other a mathematician. The latter, an eccentric, was known for collecting signatures -- signed copies of papers and books authored by visiting geniuses (Nobelists, Fields Medalists, Turing Award winners) attending the Society's Monday dinners. He would present each luminary with an ornate (strangely sticky) fountain pen and a copy of the object to be signed. Little did anyone suspect the real purpose: collecting DNA samples to be turned over to his friend for sequencing! The mathematician is later found dead under strange circumstances. Perhaps he knew too much! ...