7 What Have We Learned from GWAS?
177
some rare or low-frequency variation identified by sequencing could certainly be
integrated with findings from GWAS of complex traits in several ways; probably the
most obvious is directed (rather than genome-wide) hypothesis testing for specific
genes that segregate common variation implicated in the traits. Thus, methods,
which expand the inference process to include both common and rare genetic
variation from human studies, along with functional or other genomics information,
should certainly be anticipated in the coming years.
7.5
Closing Thoughts
The field of human genetics is now engaged in systematically validating theoretical
models worked out 100 years ago by R.A. Fisher, A.H. Sturtevant, T.H. Morgan,
and many others, whose work formulated an expectation for the architecture of
complex traits. In large part, the exciting time we live is due to the successful
application of genome-wide studies that has characterized genetic variation in large
numbers of individuals and tested for association in relatively unbiased (with respect
to underlying biology) ways. Beyond the scientific merits of the approach, the
systematic application of this central idea across a range of traits and diseases
continues to revolutionize not only the business of how such science can be
accomplished efficiently (in terms of technology and partnerships with industry)
but also the social dynamics of how science is accomplished (e.g., the increasing
emphasis on large, collaborative scientific activities and the public dissemination of
results from large-scale studies).
In the process of embarking on genome-wide studies of common variation,
development by the community of clear standards, pipelines, and rigor for how to
relate genetic variation to complex traits has clear implications for the next wave of
study designs and technologies. It is the case that next-generation sequencing studies
have a number of very specific technical challenges that did not challenge genomewide studies of common variants. As a result, these studies have an extra layer of
complexity and challenge associated with them. However, we enter the development
of new pipelines and best practices; we can take comfort in the knowledge that
there are genetic discoveries to be made. The lessons learned along with best
practices learned from GWAS give a basal understanding of what to watch out for,
an expectation for the distribution of alleles (and regions of the genome implicated
in disease), and open questions which the next wave of experimental practices are
extraordinarily well-suited to answer.
At this stage, it is possible now to envision a world in the near future where a
large number of practically actionable insights have been made across a range of
traits, leading to new and improved interventions, risk prediction, and modalities
for prevention. However, it is equally clear that much scientific ground remains to
be traversed before that vision can be fully realized. There is the unique opportunity
to translate established genetic findings into credible insight into the structure and
mechanism underlying human traits and pathophysiology of disease. If successfully
applied, these insights have the potential to radically and positively impact human
177
some rare or low-frequency variation identified by sequencing could certainly be
integrated with findings from GWAS of complex traits in several ways; probably the
most obvious is directed (rather than genome-wide) hypothesis testing for specific
genes that segregate common variation implicated in the traits. Thus, methods,
which expand the inference process to include both common and rare genetic
variation from human studies, along with functional or other genomics information,
should certainly be anticipated in the coming years.
7.5
Closing Thoughts
The field of human genetics is now engaged in systematically validating theoretical
models worked out 100 years ago by R.A. Fisher, A.H. Sturtevant, T.H. Morgan,
and many others, whose work formulated an expectation for the architecture of
complex traits. In large part, the exciting time we live is due to the successful
application of genome-wide studies that has characterized genetic variation in large
numbers of individuals and tested for association in relatively unbiased (with respect
to underlying biology) ways. Beyond the scientific merits of the approach, the
systematic application of this central idea across a range of traits and diseases
continues to revolutionize not only the business of how such science can be
accomplished efficiently (in terms of technology and partnerships with industry)
but also the social dynamics of how science is accomplished (e.g., the increasing
emphasis on large, collaborative scientific activities and the public dissemination of
results from large-scale studies).
In the process of embarking on genome-wide studies of common variation,
development by the community of clear standards, pipelines, and rigor for how to
relate genetic variation to complex traits has clear implications for the next wave of
study designs and technologies. It is the case that next-generation sequencing studies
have a number of very specific technical challenges that did not challenge genomewide studies of common variants. As a result, these studies have an extra layer of
complexity and challenge associated with them. However, we enter the development
of new pipelines and best practices; we can take comfort in the knowledge that
there are genetic discoveries to be made. The lessons learned along with best
practices learned from GWAS give a basal understanding of what to watch out for,
an expectation for the distribution of alleles (and regions of the genome implicated
in disease), and open questions which the next wave of experimental practices are
extraordinarily well-suited to answer.
At this stage, it is possible now to envision a world in the near future where a
large number of practically actionable insights have been made across a range of
traits, leading to new and improved interventions, risk prediction, and modalities
for prevention. However, it is equally clear that much scientific ground remains to
be traversed before that vision can be fully realized. There is the unique opportunity
to translate established genetic findings into credible insight into the structure and
mechanism underlying human traits and pathophysiology of disease. If successfully
applied, these insights have the potential to radically and positively impact human