Lessons from studying monogenic disease for common disease
Abstract
The prevailing paradigm for common disease emphasizes the role of common variants predisposing to various rampant health problems, and these genetic risk profiles interact with environmental and life style risk factors triggering the disease process and modifying its progress. However, most of what we know about the molecular background of common diseases is in fact based on what we have learned from rare familial forms of these traits. Further, often the mutations identified in even more rare monogenic diseases sharing some trait components with common diseases have exposed critical new pathways involved in the molecular pathogenesis of common health problems. In this review, we aim to exemplify some of the lessons learned from rare Mendelian forms of diseases that have significantly contributed to our understanding of the genetic background of common diseases and their trait components. Identification and characterization of different mutations in Mendelian variants of common traits have been extremely successful with improved accuracy of genome-wide analyses provided by the Genome Project. These, usually rare single gene disorders masquerade a multifactorial trait in their clinical phenotype, but careful data collection of family history (Mendelian segregation in a family), and detailed clinical examination (the cases are exceptionally severe or deviate otherwise from the typical disease cases) have revealed the exceptionally strong genetic character of the trait. Typically, linkage and association studies in such families have guided to a gene responsible for the disease in those particular families. Usually the mutations identified have been nearly family-specific and their value in clinical diagnosis has remained modest. Neither have they explained the majority of cases at the population level. However, by studying these ‘human allelic knockouts’ a unique view into the pathophysiology involved has been obtained. Table 1 provides a list of examples for which rare Mendelian forms of common diseases have resulted in the identification of disease genes and subsequent functional studies have evidenced their relevance for common traits. Informative examples among them include familial Alzheimer's disease (AD), MODY(s) (maturity onset diabetes of the young), familial combined hyperlipidemia (FCHL) and rare familial forms of epilepsies and migraine. These disorders, characterized by their distinct heritability have opened new avenues in further evaluation of the more common forms of dementia, diabetes, dyslipidemias and common forms of epilepsy and migraine.
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Unlike common diseases, the clarity of causation for Mendelian disorders usually simplifies generating models to connect genotype to organismal phenotype, and these models have led to critical insights into human health and disease biology.
“Unlike common diseases, the clarity of causation for Mendelian disorders usually simplifies the task of generating models (including human cells and organoids or rodents) to connect genotype to organismal phenotype; these have led to many critical insights into the biology of health and disease in humans98,99.”
From A brief history of human disease genetics (2020) · cites this paper as [99]
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“Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology.”
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“INTRODUCTION The study of rare monogenic disorders has yielded a number of insights into the molecular mechanisms underlying the pathobiology of more common diseases [1, 2].”
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“Studying rare Mendelian disorders that share their phenotype with a common disease has been successful in elucidating the molecular background in these diseases; examples include familial forms of Alzheimer’s disease, diabetes, hypertension, and dyslipidemia [32].”
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“This is because genetic backgrounds of monogenic diseases identified using Mendelian approaches can be used for studies of complex diseases to identify genetic variants not previously suspected to be associated with them and to detect pathogenic mechanisms in a variety of complex disorders.(9,10) In complex disorders…”
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“51,52 Inherited hemoglobin disorders are monogenic diseases that are commonly noted worldwide, and they include thalas-semia and SCD. Mutations in the hemoglobin β subunit gene cause SCD and TDT, the most familiar single-gene genetic disorders.”
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“Indeed, the unraveling of rare monogenic disorders has in many cases illuminated the pathogenesis of commoner complex diseases, including cancers, neurodegenerative conditions, and diabetes [Peltonen et al., 2006] Pedigree-based linkage studies have led to the identification of many autosomal dominant disease genes.”
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- Authors
- Peltonen, L., Perola, M., Naukkarinen, J., & Palotie, A.
- Affiliations
- University of Helsinki (FI)
- Broad Institute (US)
- Corresponding author
- Peltonen, Leena
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-04-15
- Volume
- 15
- Issue
- suppl_1
- Pages
- R67-R74
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2114161752
- Cited by
- 105
- References
- 49
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 1 · 2016: 4 · 2015: 6 · 2014: 3 · 2013: 5 · 2012: 5
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Academy of Finland (#213506)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL70150-01A1, R01HL070150)
- National Institute of Neurological Disorders and Stroke (R01NS43559, R01 NS37675, R01NS043559, R01NS037675)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- monogenic disorders, common diseases, Mendelian inheritance, rare variants, familial Alzheimer's disease, maturity-onset diabetes of the young, familial combined hyperlipidemia, familial epilepsy, familial migraine, disease gene identification, genetic risk factors, molecular pathogenesis
- MeSH terms
- Alzheimer Disease, Animals, Blood Pressure, Diabetes Mellitus, Humans, Models, Biological, Mutation, Gene Rearrangement, Genetic Predisposition to Disease, Multifactorial Inheritance, Genetic Diseases, Inborn, Databases, Genetic, Lipid Metabolism
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