Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1,2,3,4,5,6,7 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 estimates8,9,10,11,12. We sequenced seven genes for maturity-onset diabetes of the young (MODY)13 in well-phenotyped population samples14,15 (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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Collins, F.S. Shattuck lecture—medical and societal consequences of the Human Genome Project. N. Engl. J. Med. 341, 28–37 (1999).
Collins, F.S. Genetics: an explosion of knowledge is transforming clinical practice. Geriatrics 54, 41–47, quiz 48 (1999).
Roses, A.D. Pharmacogenetics and the practice of medicine. Nature 405, 857–865 (2000).
Hall, Y. Coming Soon: Your Personal DNA Map? National Geographic News 〈http://news.nationalgeographic.com/news/2006/03/0307_060307_dna.html〉 (2006).
Duncan, D.E. On a Mission to Sequence the Genomes of 100,000 People. New York Times (7 June 2010).
Brunham, L.R. & Hayden, M.R. Medicine. Whole-genome sequencing: the new standard of care? Science 336, 1112–1113 (2012).
Ball, M.P. et al. A public resource facilitating clinical use of genomes. Proc. Natl. Acad. Sci. USA 109, 11920–11927 (2012).
Begg, C.B. On the use of familial aggregation in population-based case probands for calculating penetrance. J. Natl. Cancer Inst. 94, 1221–1226 (2002).
Beutler, E., Felitti, V.J., Koziol, J.A., Ho, N.J. & Gelbart, T. Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359, 211–218 (2002).
Göring, H.H., Terwilliger, J.D. & Blangero, J. Large upward bias in estimation of locus-specific effects from genomewide scans. Am. J. Hum. Genet. 69, 1357–1369 (2001).
Guey, L.T. et al. Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants. Genet. Epidemiol. 35, 236–246 (2011).
Terwilliger, J.D. & Weiss, K.M. Confounding, ascertainment bias, and the blind quest for a genetic 'fountain of youth'. Ann. Med. 35, 532–544 (2003).
Molven, A. & Njolstad, P.R. Role of molecular genetics in transforming diagnosis of diabetes mellitus. Expert Rev. Mol. Diagn. 11, 313–320 (2011).
Kannel, W.B., Feinleib, M., McNamara, P.M., Garrison, R.J. & Castelli, W.P. An investigation of coronary heart disease in families. The Framingham offspring study. Am. J. Epidemiol. 110, 281–290 (1979).
Sempos, C.T., Bild, D.E. & Manolio, T.A. Overview of the Jackson Heart Study: a study of cardiovascular diseases in African American men and women. Am. J. Med. Sci. 317, 142–146 (1999).
Begg, C.B. et al. Variation of breast cancer risk among BRCA1/2 carriers. J. Am. Med. Assoc. 299, 194–201 (2008).
Kohane, I.S., Hsing, M. & Kong, S.W. Taxonomizing, sizing, and overcoming the incidentalome. Genet. Med. 14, 399–404 (2012).
Tattersall, R.B. Mild familial diabetes with dominant inheritance. Q. J. Med. 43, 339–357 (1974).
Tattersall, R.B. & Fajans, S.S. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 24, 44–53 (1975).
Murphy, R., Ellard, S. & Hattersley, A.T. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat. Clin. Pract. Endocrinol. Metab. 4, 200–213 (2008).
Eide, S.A. et al. Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 Study). Diabet. Med. 25, 775–781 (2008).
Ledermann, H.M. Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? Lancet 345, 648 (1995).
Shields, B.M. et al. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 53, 2504–2508 (2010).
Shepherd, M. et al. No deterioration in glycemic control in HNF-1α maturity-onset diabetes of the young following transfer from long-term insulin to sulphonylureas. Diabetes Care 26, 3191–3192 (2003).
Shepherd, M. & Hattersley, A.T. 'I don't feel like a diabetic any more': the impact of stopping insulin in patients with maturity onset diabetes of the young following genetic testing. Clin. Med. (Northfield IL) 4, 144–147 (2004).
Shepherd, M. et al. Predictive genetic testing in maturity-onset diabetes of the young (MODY). Diabet. Med. 18, 417–421 (2001).
McCarthy, M.I. Genomics, type 2 diabetes, and obesity. N. Engl. J. Med. 363, 2339–2350 (2010).
Knowler, W.C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).
Knowler, W.C. et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 374, 1677–1686 (2009).
Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455–458 (1996).
Hattersley, A.T. et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet 339, 1307–1310 (1992).
Froguel, P. et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N. Engl. J. Med. 328, 697–702 (1993).
Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458–460 (1996).
Horikawa, Y. et al. Mutation in hepatocyte nuclear factor-1β gene (TCF2) associated with MODY. Nat. Genet. 17, 384–385 (1997).
Stoffers, D.A., Ferrer, J., Clarke, W.L. & Habener, J.F. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat. Genet. 17, 138–139 (1997).
Molven, A. et al. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 57, 1131–1135 (2008).
Malecki, M.T. et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat. Genet. 23, 323–328 (1999).
Flanagan, S.E. et al. Update of mutations in the genes encoding the pancreatic beta-cell K (ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum. Mutat. 30, 170–180 (2009).
Plengvidhya, N. et al. PAX4 mutations in Thais with maturity onset diabetes of the young. J. Clin. Endocrinol. Metab. 92, 2821–2826 (2007).
Borowiec, M. et al. Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc. Natl. Acad. Sci. USA 106, 14460–14465 (2009).
Neve, B. et al. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc. Natl. Acad. Sci. USA 102, 4807–4812 (2005).
Raeder, H. et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat. Genet. 38, 54–62 (2006).
Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat. Biotechnol. 27, 182–189 (2009).
Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).
Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).
Abecasis, G.R. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Kumar, P., Henikoff, S. & Ng, P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).
Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).
Stenson, P.D. et al. The Human Gene Mutation Database: 2008 update. Genome Med. 1, 13 (2009).
Xue, Y. et al. Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Am. J. Hum. Genet. 91, 1022–1032 (2012).
MacArthur, D.G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012).
Srinivasan, B.S. et al. A universal carrier test for the long tail of Mendelian disease. Reprod. Biomed. Online 21, 537–551 (2010).
Arthur, C. Mapping the Individual—Cheaply. The Guardian (23 April 2008).
Pinker, S. My Genome, My Self. New York Times (7 January 2009).
Rochman, B. The DNA dilemma: a test that could change your life. TIME Magazine (2012).
Lango Allen, H. et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat. Genet. 44, 20–22 (2012).
Johansson, S. et al. Exome sequencing and genetic testing for MODY. PLoS ONE 7, e38050 (2012).
Eide, S.A. et al. Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 Study). Diabetic Med. 25, 775–81 (2008).
Ellard, S., Bellanne-Chantelot, C. & Hattersley, A.T. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 51, 546–553 (2008).
World Health Organization. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycaemia: Report of a WHO/IDF Consultation (World Health Organization Press, Geneva, 2006).
Edghill, E.L. et al. Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with Type 2 diabetes. Diabet. Med. 28, 681–684 (2011).
Gill-Carey, O., Shields, B., Colclough, K., Ellard, S. & Hattersley, A. Finding a glucokinase mutation alters patient treatment. Diabetic Med. 24 (suppl. 1), 6 (2007).
Pearson, E.R. et al. Beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1α and glucokinase mutations. Diabetes 50 (suppl. 1), S101–S107 (2001).
Stride, A. et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia 45, 427–435 (2002).
Bergmann, A. et al. The A98V single nucleotide polymorphism (SNP) in hepatic nuclear factor 1α (HNF-1α) is associated with insulin sensitivity and beta-cell function. Exp. Clin. Endocrinol. Diabetes 116 (suppl. 1), S50–S55 (2008).
Iwasaki, N. et al. Liver and kidney function in Japanese patients with maturity-onset diabetes of the young. Diabetes Care 21, 2144–2148 (1998).
McLaren, W. et al. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 26, 2069–2070 (2010).
Bach, I. et al. Cloning of human hepatic nuclear factor 1 (HNF1) and chromosomal localization of its gene in man and mouse. Genomics 8, 155–164 (1990).
Chartier, F.L., Bossu, J.P., Laudet, V., Fruchart, J.C. & Laine, B. Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver. Gene 147, 269–272 (1994).
Abbott, C. et al. Mapping of the gene TCF2 coding for the transcription factor LFB3 to human chromosome 17 by polymerase chain reaction. Genomics 8, 165–167 (1990).
Leonard, J. et al. Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. Mol. Endocrinol. 7, 1275–1283 (1993).
Sanger, F. Chemistry of insulin; determination of the structure of insulin opens the way to greater understanding of life processes. Science 129, 1340–1344 (1959).
Tamimi, R. et al. The NEUROD gene maps to human chromosome 2q32 and mouse chromosome 2. Genomics 34, 418–421 (1996).
Dawber, T.R., Meadors, G.F. & Moore, F.E. Jr. Epidemiological approaches to heart disease: the Framingham Study. Am. J. Public Health Nations Health 41, 279–281 (1951).
Berglund, G. et al. Long-term outcome of the Malmo preventive project: mortality and cardiovascular morbidity. J. Intern. Med. 247, 19–29 (2000).
Lindholm, E., Agardh, E., Tuomi, T., Groop, L. & Agardh, C.D. Classifying diabetes according to the new WHO clinical stages. Eur. J. Epidemiol. 17, 983–989 (2001).
Groop, L. et al. Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 45, 1585–1593 (1996).
Byrne, M.M. et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes 45, 1503–1510 (1996).
Bick, A.G. et al. Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. Am. J. Hum. Genet. 91, 513–519 (2012).
Li, H. & Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589–595 (2010).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
DePristo, M.A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Meyer, L.R. et al. The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res. 41, D64–D69 (2013).
Lindner, T.H. et al. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1β. Hum. Mol. Genet. 8, 2001–2008 (1999).
Njølstad, P.R. et al. Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 52, 2854–2860 (2003).
Bjørkhaug, L. et al. Hepatocyte nuclear factor-1α gene mutations and diabetes in Norway. J. Clin. Endocrinol. Metab. 88, 920–931 (2003).
Sagen, J.V. et al. Diagnostic screening of NEUROD1 (MODY6) in subjects with MODY or gestational diabetes mellitus. Diabetic Med. 22, 1012–1015 (2005).
Raeder, H. et al. A hepatocyte nuclear factor-4α gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: studies of HNF4A variants in the Norwegian MODY registry. Diabetes 55, 1899–1903 (2006).
Sagen, J.V. et al. From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation. Diabetes 55, 1713–1722 (2006).
Haldorsen, I.S. et al. Lack of pancreatic body and tail in HNF1B mutation carriers. Diabetic Med. 25, 782–787 (2008).
Sagen, J.V. et al. Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry. Pediatr. Diabetes 9, 442–449 (2008).
We acknowledge the contribution of the participants of the Framingham and Jackson Heart Study, as well as the participants from the Malmö Preventive Project, the Scania Diabetes Registry and the Botnia Study. This work was supported by grants from the National Human Genome Research Institute of the US National Institutes of Health (NIH) (Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, E. Lander) and the Howard Hughes Medical Institute, as well as funding from Pfizer Inc. J.F. was supported in part by NIH training grant 5-T32-GM007748-33. N.L.B. was supported by a Fulbright Diabetes UK Fellowship (BDA 11/0004348). D.A. was supported by funding from the Doris Duke Charitable Foundation (2006087). J.M. acknowledges support from National Institute of Diabetes and Digestive and Kidney Diseases grant K24 DK080140. J.B.M. and J.C.F. acknowledge support from NIH grant R01 DK078616. A.G.B. and V.A. were supported by NIH Medical Scientist Training Program fellowship T32GM007753. J.G.S. and C.E.S. were supported by NIH RO1 2R01HL080494, the National Heart, Lung, and Blood Institute (NHLBI) and the LeDucq Foundation. The Jackson Heart Study is supported by contracts N01-HC-95170, N01-HC-95171 and N01-HC-95172 from the NHLBI, the National Institute for Minority Health and Health Disparities and additional support from the National Institute of Biomedical Imaging and Bioengineering. The Framingham Heart Study was supported by contracts N01-HC-25195 and 6R01-NS 17950 from the NHLBI and genotyping services from Affymetrix, Inc. (contract N02-HL-6-4278 for the SNP Health Association Resource, SHARe, project). The Malmö Preventive Project and the Scania Diabetes Registry were supported by a Swedish Research Council grant (Linné) to the Lund University Diabetes Centre. The Botnia study was supported by funding from the Sigrid Juselius Foundation and the Folkhälsan Research Foundation, as well as a European Research Council advanced research grant to L.G. (GA 269045). The MODY study was supported by grants from the KG Jebsen Foundation, the Norwegian Research Council, the University of Bergen, Helse Vest, Innovest and the European Research Council (AdG).
M.J.B., J.K.T. and T.R. are employees of Pfizer, Inc. F.B. and D.R.C. are former employees of Pfizer, Inc.; F.B. retains shares in the company.
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Flannick, J., Beer, N., Bick, A. et al. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat Genet 45, 1380–1385 (2013). https://doi.org/10.1038/ng.2794
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