While there have been countless studies of the genetics of human diseases, both complex and Mendelian, relatively little work has been performed on non-disease phenotypes that affect the everyday lives of healthy individuals. One of the current major challenges in human genetic research is therefore to integrate genomics more fully with general human physiology and phenotypes that extend beyond the clinical endpoints that have been the focus of so much study. The characterization of such non-disease phenotypes is the primary motivation of our work. A prime example is intelligence: it is arguably the most interesting human trait, yet no genetic variants have yet been identified that influence i in healthy volunteers, and no whole-genome or whole-exome sequencing studies have yet attempted to unravel it. We have already collected DNA, detailed demographic information and performance on a diverse battery of cognitive tests in a cohort of 1,400 healthy volunteers;we propose to expand this sample size to 2,100. In addition to our primary focus on cognitive abilities, we have also chosen to research other genetically understudied, non-disease traits that are easy to measure, involve neuronal function, have the potential to better inform us about human diseases and are either known to be heritable or have a clear biological basis. We are proposing to use standardized, reliable tests to measure time perception, face recognition, auditory pitch discrimination, night vision abilities, and susceptibility to contagious yawning in our participants. Each of these traits is known to have a functional impact on health states, for example night vision on the ability of the elderly to remain independent, or to be impaired in certain diseases, for example time perception and contagious yawning in schizophrenia. The establishment of this cohort and phenotyping program will be of immense utility in the eventual characterization of the genetic contributions to normal variation in such traits. In an initial exploratory genetic analysis, we will sequence the exomes of 140 participants of European ethnicity who have been assessed for performance on all of these tests, restricting to those who are in the top or bottom 10% of the distribution for cognitive performance. Likelihood-based analyses will compare these exomes to each other and to the >1,500 control genomes and exomes available in our center. Variants will be prioritized for follow up genotyping based on functional annotation, frequency and the statistical evidence supporting their influence. While the power for definitive discovery is low in the initial sequenced dataset, we will leverage our cohort's frequent use as controls in other studies to cheaply genotype approximately 2,000 identified variants of interest in the remaining 1,960 participants, plus an additional 809 individuals with more limited cognitive data available, providing 80% power to identify variants explaining at least 2.5% of the variation in these traits (1% for cognition). This design therefore yields great potential to discover genetic variation influencing biologically relevant traits, increasing our understanding of the pathways underlying normal human variation and providing insight to disease.
While extensive efforts continue to be made to understand the genetics of human diseases, there has been much less serious effort dedicated to understanding the genetic bases of traits comprising everyday differences among healthy individuals, many of which are of great interest biologically and have the potential to further our understanding of diseases. Here, we propose a study of normal differences between healthy individuals, with a focus on traits that are relevant to disease, easy to measure and that involve neuronal processes. We believe that our study will provide a novel viewpoint in the biology underlying human diseases, especially as several of our traits of interest have a direct impact on quality of life and mental state.
|Bartholomew, Alex J; Lad, Eleonora M; Cao, Dingcai et al. (2016) Individual Differences in Scotopic Visual Acuity and Contrast Sensitivity: Genetic and Non-Genetic Influences. PLoS One 11:e0148192|
|Zhu, Xiaolin; Petrovski, SlavÃ©; Xie, Pingxing et al. (2015) Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med 17:774-81|
|Petrovski, SlavÃ©; Gussow, Ayal B; Wang, Quanli et al. (2015) The Intolerance of Regulatory Sequence to Genetic Variation Predicts Gene Dosage Sensitivity. PLoS Genet 11:e1005492|
|Bartholomew, Alex J; Meck, Warren H; Cirulli, Elizabeth T (2015) Analysis of Genetic and Non-Genetic Factors Influencing Timing and Time Perception. PLoS One 10:e0143873|
|GÃ³mez-Herreros, Fernando; Schuurs-Hoeijmakers, Janneke H M; McCormack, Mark et al. (2014) TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat Genet 46:516-21|
|Bartholomew, Alex J; Cirulli, Elizabeth T (2014) Individual variation in contagious yawning susceptibility is highly stable and largely unexplained by empathy or other known factors. PLoS One 9:e91773|