This coming weekend, on Saturday, September 20th, the Clinic for Special Children (CSC) in Lancaster County will hold the last in a series of auctions to benefit and honor the clinic’s 25th anniversary. Complex and colorful Amish quilts are the highlight of the items that will be sold. The multi-disciplinary clinic serves mostly the Amish and Mennonite communities of Pennsylvania, but their work has broader application:
Our approach to the care of patients with genetic disorders has wide medical relevance. Although we find “new” genetic disorders in the Amish and Mennonite populations, these disorders are not unique to the Plain populations. They are typical of genetic problems found throughout the world, problems which our clinical and laboratory experiences help solve.
Perelman School genetics professor Maja Bucan, PhD, told me of her deep appreciation for the work going on at the clinic: “From my first visit to the clinic, I knew I wanted to be part of their team as a collaborator.”
While the clinic is specializing in a wide range of medical conditions, Bucan collaborates on the genetics of mental illness using a “legacy collection.” All of the samples are from a large Old Order Amish pedigree from Lancaster County, PA, collected over the last 30 years by Janice Egeland, PhD, a Penn undergraduate alumna and professor emerita at the Miami University Miller School of Medicine. These samples were donated to the NIH-supported Cell Repository at the
Coriell Institute for Medical Research.
Earlier this year, Bucan and her colleagues from Weill Cornell Medical College and the Translational Genomics Research Institute found, using whole genome sequencing of established cell lines from the Amish blood samples, that bipolar disorder is more genetically heterogeneous than previously thought. Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite many studies aimed at characterizing the genetic underpinnings of the disorder, the risk factors causing it remain a mystery.
The study, published in PLOS Genetics, revealed that the disorder is more complex genetically than previous studies have found and that different sets of families studied have a different genetic basis for bipolar disorder. The team found five chromosome regions with multiple genes that underlie risk for bipolar disorder.
“The striking heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders,” notes Bucan. “Clinicians need to take this heterogeneity into account when diagnosing and prescribing patients’ medicine.”
Different forms of bipolar disorder are distinguished by, for example, responsiveness to lithium, the presence of seizures, and an overlap with other mental illnesses such as schizophrenia. Understanding the disorder’s genetic 
foundation could help distinguish among disease sub-types. The present investigation looked at a form of bipolar disorder that is responsive to lithium.
Recently, Kevin Strauss, MD and colleagues at the CSC led a collaboration which included Bucan and a Penn physiologist Toshinori Hoshi, PhD. They found that many individuals with mental illness in the Lancaster Amish have a mutation in the KCNH7 gene that has an important role in brain function. This mutation leads to a functional difference in the electrical properties of the ion channel protein in nerve cells, which is associated with disease. This population-based study was published in Human Molecular Genetics.
Bipolar illness in the Amish, as in the general population, is a highly complex disorder. There are many Amish subjects who have this mutation and do not have the disease, and there are Amish subjects who are bipolar who do not carry this mutation. What’s more, this mutation on its own is not sufficient to fully explain disease origin. However, the KCNH7 mutation seems to be an important piece of the puzzle.
Hoshi, who was asked to join the study prior to knowing Penn colleague Bucan was involved, says, “the big question that remains is what do these electrophysiological differences in ion channel biology mean for behavioral and developmental symptoms in patients with bipolar disorder.”
For the last 10 years, investigators have looked at the genetic basis of disease using genome-wide association studies in a large number of unrelated, affected, and unaffected individuals. But these studies only focused on common variants of disease, which only explain a small part of the genetic risk for a given disorder. “We also need to study the less frequent variants,” says Bucan. “These mutations may be rare in the general population, but more common in a group of related people, such as these families.”
Next, the team will look at larger sample sizes and additional families, as well as compare Amish and non-Amish families, adding more pieces to the explanatory “quilt” of mental illness.