A Very Good Discussion on 'Missing Heritability Problem'

A Very Good Discussion on 'Missing Heritability Problem'

Evan Charney from Duke Institute for Brain Science, Duke University wrote an informative commentary titled -

Still Chasing Ghosts: A New Genetic Methodology Will Not Find the Missing Heritability

It touches on many issues we discuss here regarding using massive volume of data to find genetic clues for complex diseases, and talks about yet another ENCODEsque junk science project called GCTA, or Genome-wide complex trait analysis.

One of the hopes and promises of the Human Genome Sequencing Project was that it would revolutionize the understanding, diagnosis, and treatment of most human disorders.


And to date, not a single polymorphism has been reliably associated with any psychiatric disorders nor any aspect of human behavior within the normal range (e.g., differences in intelligence).

To some researchers this state of affairs has given rise to a conundrum known as the problem of missing heritability. If traits such as intelligence are reported to be 50% heritable, goes the theory, why have no genes associated with intelligence been identified?

Why does it not work? Well, we have the same culprits - (i) false positives, (ii) false model.

On false positives, here is the short summary of a paragraph with detailed description -

GCTA studies are highly vulnerable to confounding by population stratification

Genetic studies (by whatever method) that have so far purported to identify SNPs associated with one or another trait have more often than not been false positives [18-20]. A prime cause of this has been the failure of researchers to take adequately into account population stratification.

The problem of ‘false model’ is even more critical.

Further problems of GCTA

While I have focused on population stratification, there are at least two other things to note about GCTA studies. First, GCTA assumes additive genetic variance, i.e., that each polymorphism contributes a tiny amount to heritability and that the effects of all the polymorphisms can simply be added together. This ignores widespread evidence that genes influence the effects of other genes in highly complex, non-additive ways (G x G interactions), and that the environment influences the manner in which genes are transcribed in equally complex ways (G x E interactions). Second, all GCTA estimates are derived from looking only at SNPs, but SNPs are only one form of genetic polymorphism. There are numerous other kinds of prevalent genetic variations, including copy number variations, multiple copies of segments of genes, whole genes, and even whole chromosomes. There is no rational scientific reason to assume that SNPs are the only relevant, or even the most important form of genetic variation (other than the fact that SNP data is easiest to obtain).

The article received many good comments from others appalled by these wasteful stamp-collection projects. Ken Weiss, Penn State professor and long-term critic of junk sciences like ENCODE, GWAS, GCAT, etc., wrote -

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.

However, the comment by M. C. Jones summarizes the state of affairs in two sentences.

Failed paradigms have a way of slouching on from beyond the grave after theyve been declared dead, especially if they have become lucrative, prestigious, and elaborate industries supporting many livelihoods and paying the mortgages on many yachts.

We recommend the readers to go through both the article and the comments. You will find a lot to think about in the back and forth discussions.

Written by M. //