Missing heritability problem

The "missing heritability" problem is the fact that single genetic variations cannot account for much of the heritability of diseases, behaviors, and other phenotypes. This is a problem that has significant implications for medicine, since a person's susceptibility to disease may depend more on 'the combined effect of all the genes in the background than on the disease genes in the foreground', or the role of genes may have been severely overestimated.
The 'missing heritability' problem was named as such in 2008 (after the "missing baryon problem" in physics). The Human Genome Project led to optimistic forecasts that the large genetic contributions to many traits and diseases (which were identified by quantitative genetics and behavioral genetics in particular) would soon be mapped and pinned down to specific genes and their genetic variants by methods such as candidate-gene studies which used small samples with limited genetic sequencing to focus on specific genes believed to be involved, examining the SNP kinds of variants. While many hits were found, they often failed to replicate in other studies.
The exponential fall in genome sequencing costs led to the use of GWAS studies which could simultaneously examine all candidate genes in larger samples than the original finding, where the candidate-gene hits were found to almost always be false positives and only 2-6% replicate; in the specific case of intelligence candidate-gene hits, only 1 candidate-gene hit replicated, the top 25 schizophrenia candidate genes were no more associated with schizophrenia than chance, and of 15 neuroimaging hits, none did. The editorial board of "Behavior Genetics" noted, in setting more stringent requirements for candidate-gene publications, that "the literature on candidate gene associations is full of reports that have not stood up to rigorous replication...it now seems likely that many of the published findings of the last decade are wrong or misleading and have not contributed to real advances in knowledge". Other researchers have characterized the literature as having "yielded an infinitude of publications with very few consistent replications" and called for a phase out of candidate-gene studies in favor of [[polygenic scores]].
This led to a dilemma. Standard genetics methods have long estimated large heritabilities such as 80% for traits such as height or intelligence, yet none of the genes had been found despite sample sizes that, while small, should have been able to detect variants of reasonable effect size such as 1 inch or 5 IQ points. If genes have such strong cumulative effects, where were they? Several resolutions have been proposed, that the missing heritability is some combination of:
References.
[[Category:Epigenetics]]