Why endophenotype development requires families |
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Authors: | David C Glahn John Blangero |
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Institution: | (1) Free University of Berlin, Berlin, Germany |
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Abstract: | Endophenotypes are heritable quantitative traits that are associated with disease liability, can be measured in both affected
and unaffected individuals, and provide much greater power to localize and identify risk genes for mental illness than does
affection status alone. Traditionally, endophenotypic markers for psychiatric illnesses include in vivo neuroanatomic and functional magnetic resonance imaging measurements and indices of neurocognitive abilities. However, neurocognitive
and neuroimaging measures are by no means the only classes of endophenotypes that could be useful for identifying genes for
mental illness. Given the advantages of endophenotype-based strategies for elucidating the genetic underpinnings of psychiatric
disorders, it would seem prudent to develop a wide range of putative endophenotypes. In order for a measure to be considered
a valid endophenotype, it must meet a number of criteria. Specifically, the trait must (1) have moderate to high heritability,
(2) be associated with the illness, (3) be independent of clinical state, and (4) impairment must co-segregate with the illness
within a family, with non-affected family members showing impairment relative to the general population. While each of these
criteria is critical, the heritability and co-segregation requirements are really what differentiate an endophenotype from
a simple biomarker. At this time, one requires an experimental design that includes families to demonstrate both heritability
and co-segregation. The assertion that novel endophenotypes can not be fully established without family data does not preclude
work in unrelated individuals, rather that unrelated samples will only be able to nominate potential candidate endophenotypes
that subsequently need to be confirmed in family-based experiments. |
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