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<p>Although much research has focused on cognitive ability and the genetic and environmental
factors that might influence it, this aspect of human nature is still far from being
well understood. It has been well-established that certain factors such as age and
education have significant impacts on performance on most cognitive tests, but the
effects of variables such as cognitive pastimes and strategies used during testing
have generally not been assessed. Additionally, no genetic variant has yet been unequivocally
shown to influence the normal variation in cognitive ability of healthy individuals.
Candidate gene studies of cognition have produced conflicting results that have not
been replicable, and genome-wide association studies have not found common variants
with large influences on this trait.</p><p>Here, we have recruited a large cohort
of healthy volunteers (n=1,887) and administered a brief cognitive battery utilizing
diverse, common, and well-known tests. In addition to providing standard demographic
information, the subjects also filled out a questionnaire that was designed to assess
novel factors such as whether they had seen the test before, in what cognitive pastimes
they participated, and what strategies they had used during testing. Linear regression
models were built to assess the effects of these variables on the test scores. I
found that the addition of novel covariates to standard ones increased the percent
of the variation in test score that was explained for all tests; for some tests, the
increase was as high as 70%.</p><p>Next, I examined the effects of genetic variants
on test scores. I first performed a genome-wide association study using the Illumina
HumanHap 550 and 610 chips. These chips are designed to directly genotype or tag
the vast majority of the common variants in the genome. Despite having 80% power
to detect a common variant explaining at least 3-6% (depending on the test) of the
variation in the trait, I did not find any genetic variants that were significantly
associated after correction for multiple testing. This is in line with the general
findings from GWA studies that single common variants have a limited impact on complex
traits.</p><p>Because of the recent technological advances in next-generation sequencing
and the apparently limited role of very common variants, many human geneticists are
making a transition from genome-wide association study to whole-genome and whole-exome
sequencing, which allow for the identification of rarer variants. Because these methods
are currently costly, it is important to utilize study designs that have the best
chance of finding causal variants in a small sample size. One such method is the
extreme-trait design, where individuals from one or both ends of a trait distribution
are sequenced and variants that are enriched in the group(s) are identified. Here,
I have sequenced the exomes of 20 young individuals of European ethnicity: 10 that
performed at the top of the distribution for the cognitive battery and 10 that performed
at the bottom. I identified rare genetic variants that were enriched in one extreme
group as compared to the other and performed follow-up genotyping of the best candidate
variant that emerged from this analysis. Unfortunately, this variant was not found
to be associated in a larger sample of individuals. This pilot study indicates that
a larger sample size will be needed to identify variants enriched in cognition extremes.</p><p>Finally,
I assessed the effect of topiramate, an antiepileptic drug that causes marked side
effects in certain cognitive areas in certain individuals, on some of the healthy
volunteers (n=158) by giving them a 100 mg dose and then administering the cognitive
test two hours later. I compared their scores at this testing session to those at
the previous session and calculated the overall level to which they were affected
by topiramate. I found that the topiramate blood levels, which were highly dependent
on weight and the time from dosing to testing, varied widely between individuals after
this acute dose, and that this variation explained 35% of the variability in topiramate
response. A genome-wide association study of the remaining variability in topiramate
response did not identify a genome-wide significant association.</p><p>In sum, I studied
the contributions of both environmental and genetic variables to cognitive ability
and cognitive response to topiramate. I found that I could identify environmental
variables explaining large proportions of the variation in these traits, but that
I could not identify genetic variants that influenced the traits. My analysis of
genetic variants was for the most part restricted to the very common ones found on
genotyping chips, and this and other studies have generally found that single common
genetic variants do not have large affects on complex traits. As we move forward
into studies that involve the sequencing of whole exomes and genomes, genetic variants
with large effects on these complex traits may finally be found.</p>
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