Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes
Open accessAbstract
Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
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These analyses have reduced contamination of databases with variants erroneously interpreted as causal and are addressing overestimation of disease penetrance arising from historical focus on multiplex pedigrees.
“These analyses have reduced the contamination of databases with variants erroneously interpreted as causal for disease, and are addressing the overestimation of disease penetrance arising from the historical focus on multiplex pedigrees25.”
From A brief history of human disease genetics (2020) · cites this paper as [25]
The remaining 29 are suggested to be due to a combination of incomplete penetrance, late onset of disease, mild symptoms not seeking medical attention, unrecognised technical issues with sequencing or annotation, or dubious evidence to support the gene-phenotype assignment.
“We suggest that the remaining 29 are due to a combination of incomplete penetrance[12–16], late onset of disease (i.e. not yet having occurred), individuals with mild symptoms not seeking medical attention, unrecognised technical issues with sequencing or annotation (e.g. tissue specific alternative splicing), or dubious evidence to support the gene-phenotype assignment”
From Health and population effects of rare gene knockouts in adult humans with related parents (2016) · cites this paper as [12]
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Self-citationPolygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood
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- Authors
- Flannick, J., Beer, N. L., Bick, A. G., Agarwala, V., Molnes, J., Gupta, N., Burtt, N. P., Florez, J. C., Meigs, J. B., Taylor, H., Lyssenko, V., Irgens, H., Fox, E., Burslem, F., Johansson, S., Brosnan, M. J., Trimmer, J. K., Newton-Cheh, C., Tuomi, T., Molven, A., Wilson, J. G., O'Donnell, C. J., Kathiresan, S., Hirschhorn, J. N., Njølstad, P. R., Rolph, T., Seidman, J. G., Gabriel, S., Cox, D. R., Seidman, C. E., Groop, L., & Altshuler, D.
- Affiliations
- Broad Institute (US)
- University of Bergen (NO)
- Harvard University (US)
- Tougaloo College (US)
- Lund University (SE)
- Haukeland University Hospital (NO)
- University of Mississippi Medical Center (US)
- Pfizer (United States) (US)
- Brigham and Women's Hospital (US)
- University of Helsinki (FI)
- Corresponding author
- Altshuler, David
- ORCID
- Flannick, Jason
- Beer, Nicola L
- Bick, Alexander G
- Molnes, Janne
- Gupta, Namrata
- Burtt, Noël P
- Meigs, James B
- Taylor, Herman
- Lyssenko, Valeriya
- Irgens, Henrik
- Johansson, Stefan
- Molven, Anders
- Wilson, James G
- Kathiresan, Sekar
- Hirschhorn, Joel N
- Njølstad, Pål R
- Rolph, Tim
- Seidman, J G
- Gabriel, Stacey
- Cox, David R
- Seidman, Christine E
- Groop, Leif
- Altshuler, David
- Venue
- Nature Genetics
- Published
- 2013-10-06
- Volume
- 45
- Issue
- 11
- Pages
- 1380-1385
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4051627
- OpenAlex
- W2020231706
- Cited by
- 136
- References
- 92
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 12 · 2021: 9 · 2020: 13 · 2019: 15 · 2018: 12 · 2017: 16 · 2016: 21 · 2015: 11 · 2014: 11
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Diabetes UK (11/0004348)
- National Institutes of Health (n01hc95170-30-0-1, n01hc95171-31-0-1, n01hc25195-41-0-1, n01hc95172-31-0-1)
- National Heart, Lung, and Blood Institute (N01‐HC25195, N01 HC095171, N01 HC095172, N02- HL-64278, R01HL084553, N01HC95172, N01-HC-025195, N01 HC095170, N01 HC 95170, N01 HC-95171, R01HL080494, R01 2R01HL080494)
- National Human Genome Research Institute (U54HG003067)
- National Institute of General Medical Sciences (5-T32-GM007748-33, T32GM007753, T32GM007748)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078616, K24DK080140)
- National Institute of Neurological Disorders and Stroke (6R01NS17950, R01NS017950)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- maturity-onset diabetes of the young, MODY genes, rare variants, asymptomatic carriers, ascertainment bias, de novo mutations, normoglycemia, type 2 diabetes risk
- MeSH terms
- Germinal Center Kinases, Adult, Base Sequence, Chromosome Mapping, Diabetes Mellitus, Type 2, Female, Humans, Male, Middle Aged, Phenotype, Risk, Genetic Variation, Trans-Activators, Protein Serine-Threonine Kinases, Sequence Analysis, DNA, Homeodomain Proteins, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 1-beta, Hepatocyte Nuclear Factor 4, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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