Genome-wide association studies in the context of "Missing heritability problem"

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⭐ Core Definition: Genome-wide association studies

In genomics, a genome-wide association study (GWA study, or GWAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. GWA studies typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major human diseases, but can equally be applied to any other genetic variants and any other organisms.

When applied to human data, GWA studies compare the DNA of participants having varying phenotypes for a particular trait or disease. These participants may be people with a disease (cases) and similar people without the disease (controls), or they may be people with different phenotypes for a particular trait, for example blood pressure. This approach is known as phenotype-first, in which the participants are classified first by their clinical manifestation(s), as opposed to genotype-first. Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays. If there is significant statistical evidence that one type of the variant (one allele) is more frequent in people with the disease, the variant is said to be associated with the disease. The associated SNPs are then considered to mark a region of the human genome that may influence the risk of disease.

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👉 Genome-wide association studies in the context of Missing heritability problem

In genetics, the missing heritability problem refers to a difference between heritability estimates obtained from early genome-wide association studies (GWAS) and heritability estimates from twin and family data across many physical and mental traits, including diseases, behaviors, and other phenotypes.

An influential review article in 2008 noted that the amount of phenotypic variance explained by significant loci in GWAS studies up to that point was usually far less than expected based on family studies. This gap was referred to as "missing heritability". Using height as a model trait, a paper in 2010 showed that most of the missing heritability can be explained by the presence of large numbers of low variants whose effect sizes were too small to detect at the sample sizes that were then available. This conclusion has subsequently been confirmed using much larger sample sizes, including a study of 5.4 million individuals that identified around 12,000 independent variants that affect human height. While studies of height have particularly large power due to their very large sample size, other complex traits likely have similar genetic architecture. Thus, the missing heritability problem is largely resolved by the presence of tens of thousands of variants of small effects that could not be detected in early GWAS studies.

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Genome-wide association studies in the context of Biobank

A biobank is a type of biorepository that stores biological samples (usually human) for use in research. Biobanks have become an important resource in medical research, supporting many types of contemporary research like genomics and personalized medicine.

Biobanks can give researchers access to data representing a large number of people. Samples in biobanks and the data derived from those samples can often be used by multiple researchers for cross purpose research studies. For example, many diseases are associated with single-nucleotide polymorphisms. Genome-wide association studies using data from tens or hundreds of thousands of individuals can identify these genetic associations as potential disease biomarkers. Many researchers struggled to acquire sufficient samples prior to the advent of biobanks.

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Genome-wide association studies in the context of Behavioural genetics

Behavioural genetics, also referred to as behaviour genetics, is a field of scientific research that uses genetic methods to investigate the nature and origins of individual differences in behaviour. While the name "behavioural genetics" connotes a focus on genetic influences, the field broadly investigates the extent to which genetic and environmental factors influence individual differences, and the development of research designs that can remove the confounding of genes and environment.

Behavioural genetics was founded as a scientific discipline by Francis Galton in the late 19th century, only to be discredited through association with eugenics movements before and during World War II. In the latter half of the 20th century, the field saw renewed prominence with research on inheritance of behaviour and mental illness in humans (typically using twin and family studies), as well as research on genetically informative model organisms through selective breeding and crosses. In the late 20th and early 21st centuries, technological advances in molecular genetics made it possible to measure and modify the genome directly. This led to major advances in model organism research (e.g., knockout mice) and in human studies (e.g., genome-wide association studies), leading to new scientific discoveries.

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