Missing heritability and strategies for finding the underlying causes of complex disease

By Evan E. Eichler, J. Flint, Greg Gibson, A. Kong, Suzanne M. Leal, Jason H. Moore, J. Nadeau. Nature reviews genetics, 2010

1,739 citations recorded by the source corpus.

Although recent genome-wide studies have provided valuable insights into the genetic basis of human disease, they have explained relatively little of the heritability of most complex traits, and the variants identified through these studies have small effect sizes. This has led to the important and hotly debated issue of where the 'missing heritability' of complex diseases might be found. Here, seven leading geneticists offer their opinion about where this heritability is likely to lie, what this could tell us about the underlying genetic architecture of common diseases and how this could inform research strategies for uncovering genetic risk factors.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/3107276a535d17a3fb33f4af4df0f5b82296e85a

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Citations in the corpus

GCTA: a tool for genome-wide complex trait analysis. (2011, methodology): “’’ Possible explanations include a large number of common variants with small effects, rare variants with large effects, and DNA structural variation.(2,4) We recently proposed a method of estimating the total amount of phenotypic variance captured by all SNPs on the current generation of commercial”
Rare-variant association testing for sequencing data with the sequence kernel association test. (2011, background): “The advent of massively parallel sequencing(2) has transformed human genetics(3,4) and has the potential to explain some of this missing heritability through identification of trait-associated rare variants.(5) Although considerable resources have been devoted to sequence mapping and genotype callin”
Trends in insulin resistance: insights into mechanisms and therapeutic strategy (2022, background): “Despite these potential genetic correlates, variants account for only 25% to 44% of the heritability of IR.(195) Consequently, the contributions of low-frequency and rare genetic variants towards the heritability of IR have also been explored through a combination of both genome and exosome sequenci”
Genome, transcriptome and proteome: the rise of omics data and their integration in biomedical sciences (2016, positive): “missing heritability [38]); however, models incorporating all SNPs regardless of their statistical significance in GWAS, substantially improve the genetic explanation of the trait [39] for which, ultimately, the remaining missing heritability is likely explained by rare variants (therefore not captu”
Direct determination of diploid genome sequences (2016, neutral): “Contributing to this isthe incomplete elucidation of the genomic architecture of the genomes under study (Eichler et al. 2010).”
The design and construction of reference pangenome graphs with minigraph (2020, background): “Some of these variants are likely associated with phenotype [3] but are often missed or misinterpreted when we map sequence data to GRCh38, in particular with short reads [4].”
Rare and Common Variants: Twenty arguments (2011, background): “or some combination of genotypic, environmental and epigenetic interactions (the broad sense heritability model”
ACAT: A Fast and Powerful P-value Combination Method for Rare-variant Analysis in Sequencing Studies (2018, methodology): “For instance, SKAT(1,25) (the two numbers in the parentheses are the values of beta(MAF) weight parameters a1 and a2, respectively) detected more windows than SKAT(1,1) in the analyses of Lp(a) in both AA individuals and EA individuals but only detected about half of the significant windows”