We came across the hilarious paper - “Human Complex Trait Genetics in the 21st Century” - written by GWAS guru Peter M. Visscher. It reminded us of the following Monte Python video shown above.
Before you read the article, think about various real scientific disciplines and check whether anyone predicted the major advances. Did Einstein predict quantum mechanics? He did not even want to believe that ‘God played dice’ after quantum equations were derived. Did someone working on bacterial genomes predict the existence of an adaptive immune system in the form of CRISPR? Did those discovering the CRISPR adaptive immune system in bacteria (Barrangou, Horvath) themselves predict that their discoveries would lead to any use in human genetics? They argued the opposite.
Most of the life-changing scientific discoveries are discontinuous and cannot be predicted. However, the expectations are quite different in the scientific world of silly walk, also known as GWAS. In their world, everything goes according to the plan, and if not, statistical trickery comes to the rescue. A few years back, GWAS appeared to be in trouble, because none of the variants had any impact more than 1-2% in explaining heritability (“missing heritability non-problem”). Peter Visscher came to the rescue and used mathematics to claim -
The real prediction about the future of ‘human complex trait genetics in the 21st century’ was made in 2000 in the following paper. Their sixteen year old paper reads like it was written this week.
“They all talked at once, their voices insistent and contradictory and impatient, making of unreality a possibility, then a probability, then an incontrovertible fact, as people will when their desires become words.” W. Faulkner, The Sound and the Fury, 1929
There are more than a few parallels between the California gold rush and today’s frenetic drive towards linkage disequilibrium (LD) mapping based on single-nucleotide polymorphisms (SNPs). This is fuelled by a faith that the genetic determinants of complex traits are tractable, and that knowledge of genetic variation will materially improve the diagnosis, treatment or prevention of a substantial fraction of cases of the diseases that constitute the major public health burden of industrialized nations.
We wonder why Visscher and his followers never mention Weiss/Terwilliger paper given that the first point of Visscher’s paper (‘Genetic Data Will Not Be Limiting’) echoes what Weiss anticipated 16 years back.
More specific criticisms of Visscher’s article -
1. Personalized Genetics and Genomics Will Become an Integral Part of Health Care and Clinical Practice
Francis Collins predicted in 1998 that little Johnnies would go to doctor’s offices in 2010 and get their entire future told to them through genetic tests. Visscher repeating the same canard in 2016 and predicting it to happen over the 21st century sounds like a defeat.
2. Modeling Human Complex Traits in Experimental Organisms Will Become Obsolete
This is likely, but has nothing to do with GWAS. Instead major discoveries in developmental biology over the last 30 years leading to building organoids in vitro would contribute to such an outcome. Japanese scientists 1, NIH 0.
3. In Osteo Population Genetics Studies?
it will be possible to take bone samples from a number of individuals who lived 100, 200, … 10,000 years ago and infer recent natural selection as if it was in real time by tracking changes in allele frequencies of variants that are known (from modern day studies) to be associated with complex traits and fitness. It might even be possible to study G E interaction by performing gene mapping on ancestral samples, for example on femur lengths (which is a highly heritable complex trait). Dig up the bodies!
He is not making a prediction, but rather suggesting a terrible way to waste money. All it would take to make the ‘prediction’ work is one of his sidekicks writing a grant and then publishing an over-hyped paper in Nature Genetics. Suggested catchy title - “Scientists explain why GWAS scientists are so full of BS by sequencing all available dead bodies under ground”.
God bless the Hindus, who have the good sense of cremating the dead and save humanity from GWAS lunatics.
4. Genetic Data Will Not Be Limiting
Huh. We all know that the real limiting factor is grants, or public money being given to various GWAS geniuses.
I predict that the tens of millions of single nucleotide variants and the many copy number variants that currently segregate in the population will be whittled down to a much more manageable credible set of plausible causal variants. I am agnostic as to what the size of that set is going to be (ten thousand? a hundred thousand? one million?).
I agree with what is said here generally, but I dont think it will make the missing heritability (Mh) problem go away. There are too many people who for many different reasons believe that more sophisticated or greater sampling, or more extensive sequencing and analysis, and larger studies, paired with animal models, will eventually account for Mh. Whether this is a correct belief or as much a rationale for funding continual increases in study scale, is debatable.
Rare variants reflect one out that is often invoked, and they certainly require large studies of one sort or another. The question here is whether enumerating rare variants and demonstrating their causal role (if it can actually be done) will do much, especially since most rare variants will be like their more common known ones, and have very small individual effects.
Another strategy is to blame the mH on interactions. Huge studies or very clever designs may identify such interactions and evaluate their import, perhaps at least generically if not by enumeration.
So the problem will, I predict, persist. That doesnt mean the claims about how to find mH are justified.