UNIVERSITY PARK, Pa. — The genetic roots of a disease or disorder do not always grow into clear cut, easily diagnosed clinical features. Even if a parent and child have the same genetic marker implicated in an outcome, such as autism, only one may present clinically or they may both present with wildly different features. That's because a single gene does not fully explain the cause for a disease or its clinical features, according to an international team led by researchers from Penn State. They recently found that the constellation of multiple genetic changes scattered throughout a person's DNA — the person's genetic background — plays a key role in the development of complex disorders.
The study, published today (Oct. 7) in the journal Cell, also detailed how the bias implicit in selecting samples for genetic research can mask the complicated and varied nature of genetic disorders.
"Some genetic diseases are relatively simple, with an essentially one-to-one relationship between the presence of a genetic variant — or a change in a person's DNA that differs across people — and the manifestation of the trait," said Santhosh Girirajan, T. Ming Chu Professor of Genomics and head of the Department of Biochemistry and Molecular Biology in the Penn State Eberly College of Science and corresponding author of the paper. "However, many traits are more complex. We know, for example, that most disease-causing variants contribute to a variety of clinical outcomes, even among individuals carrying the same variant. In this study, we looked for patterns of secondary variants that could help explain this and eventually guide the development of more effective — potentially personalized — therapies."
Genetic variants can take many different forms. For example, a single letter of the DNA alphabet might be miscopied, like a typo; or whole words, sentences or even chapters can be deleted or inserted where they don't belong. Often, variants have little effect or go unnoticed, but occasionally a variant will disrupt something necessary, leading to disease or other developmental anomalies. Primary variants are generally those that have been previously associated with a clinical feature and may be used diagnostically. However, they often don't work alone, and their impact can be influenced by secondary variants —changes found elsewhere in a person's DNA — according to Girirajan.
Girirajan and his team dissected the role of secondary genetic variants that can modify how a primary variant may or may not lead to specific clinical outcomes. Since secondary variants are unique to each person, the researchers said a "multi-hit" model can help explain how the variability in symptoms associated with a primary variant results from a person's individual genomic architecture.
"Our past work suggested that a primary variant sensitizes an individual for disease, and the clinical outcome is determined by secondary 'hits' elsewhere in the genome," Girirajan said. "However, it is not completely understood how specific variant classes modify clinical features across different methods of ascertainment — how sample cohorts are selected and studied — and primary variant contexts."
In genetic studies, researchers can select cohorts of interest from pools that were developed for a variety of purposes. For example, one pool may comprise only families who underwent genetic testing because they have a child with a developmental delay. Another pool may comprise primarily healthy individuals, such as national or international representative biobanks. Yet another pool may contain people with a specific clinical feature, no matter their other clinical presentations.
In this study, the team found the relationship between primary and secondary variants differed depending on whether they ascertained their study cohort from a pool of mostly healthy individuals or from a pool of individuals included for having similar clinical features, such as autism.
To investigate both how variant interplay and cohort selection informs clinical outcomes, the team focused on individuals with a deletion of a section of chromosome 16 — called 16p12.1 in reference to its location on the chromosome — associated with a variety of traits, including developmental delay, autism and psychiatric disorders. This deletion is diagnosed via genetic testing, according to the researchers, who noted that even if a parent and child both carry the deletion, they often experience different features. For example, when a child presents with severe developmental delays, the parent may exhibit psychiatric features such as depression or anxiety.
"This gives us the opportunity to ask what other genetic factors are contributing to the different outcomes of the 16p12.1 deletion that we see between individuals," said Corrine Smolen, a graduate student in the bioinformatics and genomics program at Penn State and co-first author of the paper. "In the past, we've shown that having a generally higher level of background variants in addition to the deletion leads to more severe traits, but we wanted to see if we could identify patterns between the types of variants in an individual and their specific clinical features."
The team recruited a cohort of 442 individuals from 124 families with at least one child with developmental delays and known to have the 16p12.1 deletion. The researchers used whole genome sequences and medical records from this cohort to evaluate 17 classes of secondary variants and found that certain types of variants influenced risk for specific clinical features. For example, children in the sample with an expansion in a type of variant called a short tandem repeat — where the same short sequence of DNA is found back-to-back in the genome and the number of copies of the sequence can change when passed from parent to child — had a higher risk of developing nervous system features in addition to the developmental delay.
The researchers also compared that cohort of families with a cohort of individuals with the deletion found in a selection of large population biobanks, some of which contain mostly healthy individuals and some that include individuals ascertained for autism features.
"We see a clear difference in the relationship between primary and secondary variants based on how individuals with the deletion were ascertained," Girirajan said. "People from the general population show different patterns of secondary variants and clinical features than kids with developmental delays."
While these findings limit the generalizability of the patterns of primary and secondary variants with clinical outcomes across cohorts, understanding this variation could help guide future studies and aid in the development of personalized medical approaches to address complex traits, the researchers said.
"This is what makes complex traits so difficult to study," Girirajan said. "While we still have a lot to learn, our results suggest that treatment strategies need to consider more than just the primary variant. Instead, we'll need to take a more complete approach that considers each individual person's characteristics or clinical features and their unique set of secondary variants."
In addition to Girirajan and Smolen, research team members from Penn State include graduate students Matthew Jensen, Anastasia Tyryshkina, Lucilla Pizzo, Jiawan Sun, Serena Noss, Deepro Banerjee and Vijay Kumar Pounraja; Hyebin Song, assistant professor of statistics; and research technicians Laura Rohan and Emily Huber. A full list of authors and their affiliations, representing 31 institutions from 10 countries, may be found in the paper.
The U.S. National Institutes of Health and the Penn State Huck Institutes of the Life Sciences funded the research. The project also received funding from the Oak Ridge Associated Universities under an agreement with the National Library of Medicine for analysis of All of Us data, the Fulbright Commission Uruguay-National Agency for Research and Innovation, the Swiss National Science Foundation, and the National Institute for Health and Care Research-Manchester Biomedical Research Centre.
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