Missing Heritability Problem
The missing heritability problem is the issue that phenotypes understood to be genetic have not yet had all the genes involved in determining the phenotype identified through GWAS studies. 1 GWAS, or genome-wide association studies, involve screening millions of single nucleotide polymorphisms (SNPs) for statistical association with a given phenotype. These studies have been conducted on some genetic conditions, such as breast cancers where the BRCA1 and BRCA2 (among other) genes were identified.
The complexity and size of the human genome means that it has not yet been possible to identify all the risk alleles in common variant / common disease conditions. This assumes that common genetic disorders (affecting 1-5% of the population) should be affected by common variants (or SNPs). These variants should be detected in the sample sizes used in these studies (up to ~5 million individuals). 1
This problem is likely a combination of: The flaws of twin studies. These studies likely create associations between phenotypes and genotypes that do not exist in reality. Epigenetics. There may be both genetic and environmental processes to develop a condition. Phenotypes influenced by many SNPs with medium impacts on the final condition may be hard to detect with GWA studies. Misdiagnosis by clinicians may lead to poor quality data being used in GWA studies, making it more challenging to identify risk alleles. 2