Cited by 105Genetic Associations and EpidemiologyGenomics and Rare DiseasesGenetic Mapping and Diversity in Plants and Animals

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Lessons from studying monogenic disease for common disease

Peltonen, Leena, Perola, Markus, Naukkarinen, Jussi, Palotie, Aarno·2006·Human Molecular Genetics

DOI 10.1093/hmg/ddl060

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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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Authors: Peltonen, L., Perola, M., Naukkarinen, J., & Palotie, A.
Affiliations: University of Helsinki (FI)
Broad Institute (US)
Corresponding author: Peltonen, Leena
ORCID: Peltonen, Leena
Perola, Markus
Palotie, Aarno
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
DOI: 10.1093/hmg/ddl060
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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Lessons from studying monogenic disease for common disease

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