A Nondegenerate Code of Deleterious Variants in Mendelian Loci Contributes to Complex Disease Risk

Abstract

Summary Whereas countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. Here, we examine the extent to which Mendelian variation contributes to complex disease risk by mining the medical records of over 110 million patients. We detect thousands of associations between Mendelian and complex diseases, revealing a non-degenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this “Mendelian code.” Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute non-additively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.

Dense Annotation of Free-Text Critical Care Discharge Summaries from an Indian Hospital and Associated Performance of a Clinical NLP Annotator

“…As an example, a surprising correlation between complex diseases and Mendelian loci was revealed in a recent study, where records from 100+ million patients in Denmark and the United States were analyzed [8]. In a different scenario, Li Li et al (2014) combined data from genome association studies together with EHR records to find novel trait-disease associations, such as an increase in mean corpuscular volume before the onset of acute lymphoblastic leukemia [9].…”

Textbook of Personalized Medicine

“…Role of genetic factors in the etiology of complex diseases remains largely unresolved. Using genome-wide associations in millions of patient medical records, a study demonstrated that common variants associated with complex diseases are enriched in the genes indicated by the "Mendelian code" -a phenotypic code that links each complex disorder to a unique collection of Mendelian loci (Blair et al 2013 ). The study identifi ed widespread comorbidity between Mendelian-Mendelian and Mendelian-complex disease pairs.…”

Identifying novel interventional strategies for psychiatric disorders: integrating genomics, ‘enviromics’ and gene–environment interactions in valid preclinical models

“…Co-morbidity has several consequences including complicating the dissection of the biological mechanisms responsible for the distinct disorders; however, these co-morbidities may also provide a way for accessing information on these complex disorders. This has been elegantly shown recently, by Blair and colleagues, who demonstrated an association between Mendelian disorders and other complex conditions, subsequently showing that the Mendelian variants are probably contributing to disease risk for a range of complex diseases, providing a 'unique insight into the aetiology of complex diseases' (Blair et al, 2013). Furthermore, a recent genome-wide analysis aimed at finding a signal in the noise, led to the identification of risk loci with shared effects on five major psychiatric disorders (Cross-Disorder Group of the Psychiatric Genomics Consortium, Genetic Risk Outcome of Psychosis (GROUP) Consortium, 2013).…”