The Human Microbiome and the Missing Heritability Problem

Abstract

The “missing heritability” problem states that genetic variants in Genome-Wide Association Studies (GWAS) cannot completely explain the heritability of complex traits. Traditionally, the heritability of a phenotype is measured through familial studies using twins, siblings and other close relatives, making assumptions on the genetic similarities between them. When this heritability is compared to the one obtained through GWAS for the same traits, a substantial gap between both measurements arise with genome wide studies reporting significantly smaller values. Several mechanisms for this “missing heritability” have been proposed, such as epigenetics, epistasis, and sequencing depth. However, none of them are able to fully account for this gap in heritability. In this paper we provide evidence that suggests that in order for the phenotypic heritability of human traits to be broadly understood and accounted for, the compositional and functional diversity of the human microbiome must be taken into account. This hypothesis is based on several observations: (A) The composition of the human microbiome is associated with many important traits, including obesity, cancer, and neurological disorders. (B) Our microbiome encodes a second genome with nearly a 100 times more genes than the human genome, and this second genome may act as a rich source of genetic variation and phenotypic plasticity. (C) Human genotypes interact with the composition and structure of our microbiome, but cannot by themselves explain microbial variation. (D) Microbial genetic composition can be strongly influenced by the host's behavior, its environment or by vertical and horizontal transmissions from other hosts. Therefore, genetic similarities assumed in familial studies may cause overestimations of heritability values. We also propose a method that allows the compositional and functional diversity of our microbiome to be incorporated to genome wide association studies.

Heritability jointly Explained by Host Genotype and Microbiome:Will Improve Traits Prediction?

“…In light of host-microbiome symbiosis, it is pertinent that the host genetics and microbiome be viewed as a single unit representing 'host community genotype'. Indeed, the shift towards the view of organisms as an ecosystems has been advocated [17] (see Figure 1).…”

Race, Rare Genetic Variants, and the Science of Human Difference in the Post‐Genomic Age

“…Researchers have put forward several ideas to explain why GWAS studies only detect small amounts of the heritable components of a disease: these ideas include epigenetic factors, gene interactions, and discounting the effects of the microbiome as well as population genetic parameters (Sandoval‐Motta et al. ; Simons et al. ).…”

“…This effectively means that the majority, 70%-95%, of the underlying heritable causes of disease are unknown. Researchers have put forward several ideas to explain why GWAS studies only detect small amounts of the heritable components of a disease: these ideas include epigenetic factors, gene interactions, and discounting the effects of the microbiome as well as population genetic parameters (Sandoval-Motta et al 2017;Simons et al 2018). One increasingly accepted idea involves the use of alternative disease models (Manolio et al 2009;Marian 2012;Zuk et al 2014).…”

A non-Lamarckian model for the inheritance of the epigenetically-coded phenotypic characteristics: a new paradigm for Genetics, Genomics and, above all, Ageing studies

“…The missing heritability problem is still an open question in the biological field. Many different solutions have been proposed: from the effect of the human microbiome (Sandoval-Motta et al, 2017), to the effect of epigenetic factors (Rakyan et al, 2011). None of those studies, though, question that the DNA is the only bearer of the "genetic" information.…”