Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes

Area of Science:

• Quantitative genetics
• Complex disease genetics
• Human genetics

Background:

• Complex diseases exhibit significant genetic influence on susceptibility and variability.
• A substantial portion of the genetic contribution to complex phenotypes remains unidentified, termed "missing heritability."
• Existing hypotheses for missing heritability lack definitive explanations.

Purpose of the Study:

• To propose that the genetic components of intermediate phenotypes contribute to the missing heritability of complex diseases.
• To investigate whether genetic factors influencing intermediate phenotypes are detectable at the level of the main complex trait.
• To establish the identification of genetic components in intermediate phenotypes as a strategy for uncovering missing heritability.

Main Methods:

• This study proposes a theoretical framework rather than empirical methods.
• The approach involves analyzing the genetic architecture of intermediate phenotypes.
• It focuses on the potential for genetic effects on intermediate phenotypes to be masked at the level of the final complex trait.

Main Results:

• A significant portion of missing heritability may be attributed to the genetic underpinnings of intermediate phenotypes.
• Genetic contributions to intermediate phenotypes may not be readily apparent when studying the primary complex trait.
• The genetic basis of intermediate phenotypes offers a novel avenue for explaining missing heritability.

Conclusions:

• The genetic influence on intermediate phenotypes is a plausible explanation for a portion of missing heritability in complex diseases.
• Investigating intermediate phenotypes is crucial for a comprehensive understanding of complex trait genetics.
• This approach provides a new perspective for identifying the genetic factors underlying complex diseases.