Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 6/2009

01-06-2009 | Article

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Authors: S. Lillioja, A. Wilton

Published in: Diabetologia | Issue 6/2009

Login to get access

Abstract

Aims/hypothesis

Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies.

Methods

We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic ‘hot spots’.

Results

Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result.

Conclusions/interpretation

Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.
Appendix
Available only for authorised users
Literature
1.
Abney M, Ober C, McPeek MS (2002) Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites. Am J Hum Genet 70:920–934PubMed
2.
An P, Hong Y, Weisnagel SJ et al (2003) Genomic scan of glucose and insulin metabolism phenotypes: the HERITAGE Family Study. Metab Clin Exper 52:246–253
3.
An P, Teran-Garcia M, Rice T et al (2005) Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study. Diabetologia 48:1142–1149PubMed
4.
An P, Freedman BI, Hanis CL et al (2005) Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis. Diabetes 54:909–914PubMed
5.
An P, Freedman BI, Rich SS et al (2006) Quantitative trait loci on chromosome 8q24 for pancreatic beta-cell function and 7q11 for insulin sensitivity in obese nondiabetic white and black families: evidence from genome-wide linkage scans in the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study. Diabetes 55:551–558PubMed
6.
Aulchenko YS, Vaessen N, Heutink P et al (2003) A genome-wide search for genes involved in type 2 diabetes in a recently genetically isolated population from The Netherlands. Diabetes 52:3001–3004PubMed
7.
Avery CL, Freedman BI, Heiss G et al (2004) Linkage analysis of diabetes status among hypertensive families: the Hypertension Genetic Epidemiology Network Study. Diabetes 53:3307–3312PubMed
8.
Avery CL, Freedman BI, Kraja AT et al (2006) Genotype-by-sex interaction in the aetiology of type 2 diabetes mellitus: support for sex-specific quantitative trait loci in Hypertension Genetic Epidemiology Network participants. Diabetologia 49:2329–2336PubMed
9.
Bektas A, Suprenant ME, Wogan LT et al (1999) Evidence of a novel type 2 diabetes locus 50 cM centromeric to NIDDM2 on chromosome 12q. Diabetes 48:2246–2251PubMed
10.
Bowden DW, Rudock M, Ziegler J et al (2006) Coincident linkage of type 2 diabetes, metabolic syndrome, and measures of cardiovascular disease in a genome scan of the diabetes heart study. Diabetes 55:1985–1994PubMed
11.
Broeckel U, Hengstenberg C, Mayer B et al (2002) A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat Genet 30:210–214PubMed
12.
Busfield F, Duffy DL, Kesting JB et al (2002) A genomewide search for type 2 diabetes-susceptibility genes in indigenous Australians. Am J Hum Genet 70:349–357PubMed
13.
Cai G, Cole SA, Freeland-Graves JH, MacCluer JW, Blangero J, Comuzzie AG (2004) Genome-wide scans reveal quantitative trait Loci on 8p and 13q related to insulin action and glucose metabolism: the San Antonio Family Heart Study. Diabetes 53:1369–1374PubMed
14.
Cai G, Cole SA, Butte NF, Voruganti VS, Comuzzie AG (2007) A quantitative trait locus on chromosome 13q affects fasting glucose levels in Hispanic children. J Clin Endocrinol Metab 92:4893–4896PubMed
15.
Chen G, Adeyemo A, Zhou J et al (2007) Genome-wide search for susceptibility genes to type 2 diabetes in West Africans: potential role of C-peptide. Diabetes Res Clin Pract 78:e1–6PubMed
16.
Cheng LS, Davis RC, Raffel LJ et al (2001) Coincident linkage of fasting plasma insulin and blood pressure to chromosome 7q in hypertensive Hispanic families. Circulation 104:1255–1260PubMed
17.
Chiu Y-F, Chuang L-M, Hsiao C-F et al (2005) An autosomal genome-wide scan for loci linked to pre-diabetic phenotypes in nondiabetic Chinese subjects from the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Family Study. Diabetes 54:1200–1206PubMed
18.
Cox NJ, Frigge M, Nicolae DL et al (1999) Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nat Genet 21:213–215PubMed
19.
Das SK, Hasstedt SJ, Zhang Z, Elbein SC (2004) Linkage and association mapping of a chromosome 1q21-q24 type 2 diabetes susceptibility locus in northern European Caucasians. Diabetes 53:492–499PubMed
20.
Diego VP, Goring HHH, Cole SA et al (2006) Fasting insulin and obesity-related phenotypes are linked to chromosome 2p: the Strong Heart Family Study. Diabetes 55:1874–1878PubMed
21.
Duggirala R, Blangero J, Almasy L et al (2001) A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet 68:1149–1164PubMed
22.
Duggirala R, Almasy L, Blangero J et al (2003) Further evidence for a type 2 diabetes susceptibility locus on chromosome 11q. Genet Epidemiol 24:240–242PubMed
23.
Ehm MG, Karnoub MC, Sakul H et al (2000) Genomewide search for type 2 diabetes susceptibility genes in four American populations. J Hum Genet 66:1871–1881
24.
Einarsdottir E, Mayans S, Ruikka K et al (2006) Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden. Diabetes 55:1879–1883PubMed
25.
Elbein SC, Hoffman MD, Teng K, Leppert MF, Hasstedt SJ (1999) A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes 48:1175–1182PubMed
26.
Falchi M, Wilson SG, Paximadas D, Swaminathan R, Spector TD (2008) Quantitative linkage analysis for pancreatic B cell function and insulin resistance in a large twin cohort. Diabetes 57:1120–1124PubMed
27.
Fradin D, Heath S, Lathrop M, Bougneres P (2007) Quantitative trait loci for fasting glucose in young Europeans replicate previous findings for type 2 diabetes in 2q23-24 and other locations. Diabetes 56:1742–1745PubMed
28.
Francke S, Manraj M, Lacquemant C et al (2001) A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum Mol Genet 10:2751–2765PubMed
29.
Frayling TM, Wiltshire S, Hitman GA et al (2003) Young-onset type 2 diabetes families are the major contributors to genetic loci in the Diabetes UK Warren 2 genome scan and identify putative novel loci on chromosomes 8q21, 21q22, and 22q11. Diabetes 52:1857–1863PubMed
30.
Freedman BI, Rich SS, Sale MM et al (2005) Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families. Diabetologia 48:661–668PubMed
31.
Hanis CL, Boerwinkle E, Chakraborty R et al (1996) A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13:161–166PubMed
32.
Hanson RL, Ehm MG, Pettitt DJ et al (1998) An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet 63:1130–1138PubMed
33.
Hanson RL, Imperatore G, Narayan KM et al (2001) Family and genetic studies of indices of insulin sensitivity and insulin secretion in Pima Indians. Diabetes/Metab Res Rev 17:296–303
34.
Hegele RA, Sun F, Harris SB, Anderson C, Hanley AJ, Zinman B (1999) Genome-wide scanning for type 2 diabetes susceptibility in Canadian Oji-Cree, using 190 microsatellite markers. J Hum Genet 44:10–14PubMed
35.
Hoffmann K, Mattheisen M, Dahm S et al (2007) A German genome-wide linkage scan for type 2 diabetes supports the existence of a metabolic syndrome locus on chromosome 1p36.13 and a type 2 diabetes locus on chromosome 16p12.2. Diabetologia 50:1418–1422PubMed
36.
Hsueh W-C, St Jean PL, Mitchell BD et al (2003) Genome-wide and fine-mapping linkage studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21-q24. Diabetes 52:550–557PubMed
37.
Hsueh W-C, Silver KD, Pollin TI et al (2007) A genome-wide linkage scan of insulin level derived traits: the Amish Family Diabetes Study. Diabetes 56:2643–2648PubMed
38.
Hunt KJ, Lehman DM, Arya R et al (2005) Genome-wide linkage analyses of type 2 diabetes in Mexican Americans: the San Antonio Family Diabetes/Gallbladder Study. Diabetes 54:2655–2662PubMed
39.
Iwasaki N, Cox NJ, Wang Y-Q et al (2003) Mapping genes influencing type 2 diabetes risk and BMI in Japanese subjects. Diabetes 52:209–213PubMed
40.
Kim S-H, Ma X, Weremowicz S et al (2004) Identification of a locus for maturity-onset diabetes of the young on chromosome 8p23. Diabetes 53:1375–1384PubMed
41.
Kissebah AH, Sonnenberg GE, Myklebust J et al (2000) Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 97:14478–14483PubMed
42.
Klupa T, Malecki MT, Pezzolesi M et al (2000) Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2. Diabetes 49:2212–2216PubMed
43.
Lakka TA, Rankinen T, Weisnagel SJ et al (2003) A quantitative trait locus on 7q31 for the changes in plasma insulin in response to exercise training: the HERITAGE Family Study. Diabetes 52:1583–1587PubMed
44.
Langefeld CD, Wagenknecht LE, Rotter JI et al (2004) Linkage of the metabolic syndrome to 1q23-q31 in Hispanic families: the Insulin Resistance Atherosclerosis Study Family Study. Diabetes 53:1170–1174PubMed
45.
Lehman DM, Arya R, Blangero J et al (2005) Bivariate linkage analysis of the insulin resistance syndrome phenotypes on chromosome 7q. Hum Biol 77:231–246PubMed
46.
Lembertas AV, Perusse L, Chagnon YC et al (1997) Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q. J Clin Invest 100:1240–1247PubMed
47.
Li W-D, Dong C, Li D, Garrigan C, Price RA (2004) A quantitative trait locus influencing fasting plasma glucose in chromosome region 18q22-23. Diabetes 53:2487–2491PubMed
48.
Lindgren CM, Mahtani MM, Widen E et al (2002) Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia Study. Am J Hum Genet 70:509–516PubMed
49.
Lindgren CM, Widen E, Tuomi T et al (2002) Contribution of known and unknown susceptibility genes to early-onset diabetes in Scandinavia: evidence for heterogeneity. Diabetes 51:1609–1617PubMed
50.
Lindsay RS, Kobes S, Knowler WC, Bennett PH, Hanson RL (2001) Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in Pima Indians. Diabetes 50:2850–2857PubMed
51.
Luo TH, Zhao Y, Li G et al (2001) A genome-wide search for type II diabetes susceptibility genes in Chinese Hans. Diabetologia 44:501–506PubMed
52.
Martin LJ, Comuzzie AG, Dupont S et al (2002) A quantitative trait locus influencing type 2 diabetes susceptibility maps to a region on 5q in an extended French family. Diabetes 51:3568–3572PubMed
53.
Meigs JB, Panhuysen CIM, Myers RH, Wilson PWF, Cupples LA (2002) A genome-wide scan for loci linked to plasma levels of glucose and HbA1c in a community-based sample of Caucasian pedigrees: the Framingham Offspring Study. Diabetes 51:833–840PubMed
54.
Meigs JB, Manning AK, Fox CS et al (2007) Genome-wide association with diabetes-related traits in the Framingham Heart Study. BMC Medical Genetics 8(Suppl 1):S16PubMed
55.
Mori Y, Otabe S, Dina C et al (2002) Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p. Diabetes 51:1247–1255PubMed
56.
Nawata H, Shirasawa S, Nakashima N et al (2004) Genome-wide linkage analysis of type 2 diabetes mellitus reconfirms the susceptibility locus on 11p13-p12 in Japanese. J Hum Genet 49:629–634PubMed
57.
Ng MCY, So W-Y, Lam VKL et al (2004) Genome-wide scan for metabolic syndrome and related quantitative traits in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25. Diabetes 53:2676–2683PubMed
58.
Ng MCY, So W-Y, Cox NJ et al (2004) Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25. Diabetes 53:1609–1613PubMed
59.
North KE, Franceschini N, Borecki IB et al (2007) Genotype-by-sex interaction on fasting insulin concentration: the HyperGEN Study. Diabetes 56:137–142PubMed
60.
Palmer ND, Langefeld CD, Campbell JK et al (2006) Genetic mapping of disposition index and acute insulin response loci on chromosome 11q. The Insulin Resistance Atherosclerosis Study (IRAS) Family Study. Diabetes 55:911–918PubMed
61.
Panhuysen CIM, Cupples LA, Wilson PWF, Herbert AG, Myers RH, Meigs JB (2003) A genome scan for loci linked to quantitative insulin traits in persons without diabetes: the Framingham Offspring Study. Diabetologia 46:579–587PubMed
62.
Parker A, Meyer J, Lewitzky S et al (2001) A gene conferring susceptibility to type 2 diabetes in conjunction with obesity is located on chromosome 18p11. Diabetes 50:675–680PubMed
63.
Permutt MA, Wasson JC, Suarez BK et al (2001) A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population. Diabetes 50:681–685PubMed
64.
Pezzolesi MG, Nam M, Nagase T et al (2004) Examination of candidate chromosomal regions for type 2 diabetes reveals a susceptibility locus on human chromosome 8p23.1. Diabetes 53:486–491PubMed
65.
Pratley RE, Thompson DB, Prochazka M et al (1998) An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest 101:1757–1764PubMed
66.
Reynisdottir I, Thorleifsson G, Benediktsson R et al (2003) Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2. Am J Hum Genet 73:323–335PubMed
67.
Rich SS, Bowden DW, Haffner SM et al (2004) Identification of quantitative trait loci for glucose homeostasis: the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. Diabetes 53:1866–1875PubMed
68.
Rich SS, Bowden DW, Haffner SM et al (2005) A genome scan for fasting insulin and fasting glucose identifies a quantitative trait locus on chromosome 17p: the insulin resistance atherosclerosis study (IRAS) family study. Diabetes 54:290–295PubMed
69.
Rotimi CN, Chen G, Adeyemo AA et al (2004) A genome-wide search for type 2 diabetes susceptibility genes in West Africans: the Africa America Diabetes Mellitus (AADM) Study. Diabetes 53:838–841PubMed
70.
Sale MM, Freedman BI, Langefeld CD et al (2004) A genome-wide scan for type 2 diabetes in African-American families reveals evidence for a locus on chromosome 6q. Diabetes 53:830–837PubMed
71.
Shaw JT, Lovelock PK, Kesting JB et al (1998) Novel susceptibility gene for late-onset NIDDM is localized to human chromosome 12q. Diabetes 47:1793–1796PubMed
72.
Shtir C, Nagakawa IS, Duren WL et al (2007) Subsets of Finns with high HDL to total cholesterol ratio show evidence for linkage to type 2 diabetes on chromosome 6q. Hum Hered 63:17–25PubMed
73.
Silander K, Scott LJ, Valle TT et al (2004) A large set of Finnish affected sibling pair families with type 2 diabetes suggests susceptibility loci on chromosomes 6, 11, and 14. Diabetes 53:821–829PubMed
74.
van Tilburg JH, Sandkuijl LA, Strengman E et al (2003) A genome-wide scan in type 2 diabetes mellitus provides independent replication of a susceptibility locus on 18p11 and suggests the existence of novel loci on 2q12 and 19q13. J Clin Endocrinol Metab 88:2223–2230PubMed
75.
van Tilburg JH, Sandkuijl LA, Franke L et al (2003) Genome-wide screen in obese pedigrees with type 2 diabetes mellitus from a defined Dutch population. Eur J Clin Investig 33:1070–1074
76.
Vionnet N, Hani El H, Dupont S et al (2000) Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. Am J Hum Genet 67:1470–1480PubMed
77.
Voruganti VS, Goring HHH, Diego VP et al (2007) Genome-wide scan for serum ghrelin detects linkage on chromosome 1p36 in Hispanic children: results from the Viva La Familia Study. Pediatr Res 62:445–450PubMed
78.
Watanabe RM, Ghosh S, Langefeld CD et al (2000) The Finland–United States Investigation of Non-insulin-dependent Diabetes Mellitus Genetics (FUSION) Study. II. An autosomal genome scan for diabetes-related quantitative-trait loci. Am J Hum Genet 67:1186–1200PubMed
79.
Wiltshire S, Hattersley AT, Hitman GA et al (2001) A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am J Hum Genet 69:553–569PubMed
80.
Wiltshire S, Frayling TM, Groves CJ et al (2004) Evidence from a large U.K. family collection that genes influencing age of onset of type 2 diabetes map to chromosome 12p and to the MODY3/NIDDM2 locus on 12q24. Diabetes 53:855–860PubMed
81.
Wiltshire S, Bell JT, Groves CJ et al (2006) Epistasis between type 2 diabetes susceptibility Loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans. Ann Hum Genet 70:726–737PubMed
82.
Xiang K, Wang Y, Zheng T et al (2004) Genome-wide search for type 2 diabetes/impaired glucose homeostasis susceptibility genes in the Chinese: significant linkage to chromosome 6q21-q23 and chromosome 1q21-q24. Diabetes 53:228–234PubMed
83.
Zhao JY, Xiong MM, Huang W et al (2005) An autosomal genomic scan for loci linked to type 2 diabetes in northern Han Chinese. J Mol Med 83:209–215PubMed
84.
Meigs JB, Shrader P, Sullivan LM et al (2008) Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 359:2208–2219PubMed
85.
Lyssenko V, Jonsson A, Almgren P et al (2008) Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 359:2220–2232PubMed
86.
Kent WJ, Sugnet CW, Furey TS et al (2002) The human genome browser at UCSC. Genome Res 12:996–1006PubMed
87.
Frayling TM (2007) Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev, Genet 8:657–662
88.
Yasuda K, Miyake K, Horikawa Y et al (2008) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 40:1092–1097PubMed
89.
Zeggini E, Scott LJ, Saxena R et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645PubMed
90.
Sham P (1997) Statistics in human genetics. Arnold, London
91.
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247PubMed
92.
Risch NJ (2000) Searching for genetic determinants in the new millennium. Nature 405:847–856PubMed
93.
Wiltshire S, Cardon LR, McCarthy MI (2002) Evaluating the results of genomewide linkage scans of complex traits by locus counting. Am J Hum Genet 71:1175–1182PubMed
94.
Mills GW, Avery PJ, McCarthy MI et al (2004) Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes. Diabetologia 47:732–738PubMed
95.
Hong Y, Weisnagel SJ, Rice T et al (2001) Familial resemblance for glucose and insulin metabolism indices derived from an intravenous glucose tolerance test in Blacks and Whites of the HERITAGE Family Study. Clin Genet 60:22–30PubMed
96.
Li JKY, Ng MCY, So WY et al (2006) Phenotypic and genetic clustering of diabetes and metabolic syndrome in Chinese families with type 2 diabetes mellitus. Diabetes/Metab Rev 22:46–52
97.
Lyssenko V, Almgren P, Anevski D et al (2005) Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes 54:166–174PubMed
98.
Hara H, Egusa G, Yamakido M (1996) Incidence of non-insulin-dependent diabetes mellitus and its risk factors in Japanese-Americans living in Hawaii and Los Angeles. Diabet Med 13:S133–S142PubMed
99.
Hanson RL, Pratley RE, Bogardus C et al (2000) Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol 151:190–198PubMed
100.
Elbein SC, Hasstedt SJ, Wegner K, Kahn SE (1999) Heritability of pancreatic beta-cell function among nondiabetic members of Caucasian familial type 2 diabetic kindreds. J Clin Endocrinol Metab 84:1398–1403PubMed
101.
Bergman RN, Zaccaro DJ, Watanabe RM et al (2003) Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin. Diabetes 52:2168–2174PubMed
102.
Rasmussen-Torvik LJ, Pankow JS, Jacobs DR et al (2007) Heritability and genetic correlations of insulin sensitivity measured by the euglycaemic clamp. Diabet Med 24:1286–1289PubMed
103.
Guan W, Pluzhnikov A, Cox NJ, Boehnke M, International Type 2 Diabetes Linkage Analysis C (2008) Meta-analysis of 23 type 2 diabetes linkage studies from the International Type 2 Diabetes Linkage Analysis Consortium. Hum Hered 66:35–49PubMed
104.
Kong A, Gudbjartsson DF, Sainz J et al (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247PubMed
105.
Kruglyak L, Lander ES (1995) Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 57:439–454PubMed
106.
Cordell HJ (2001) Sample size requirements to control for stochastic variation in magnitude and location of allele-sharing linkage statistics in affected sibling pairs. Ann Hum Genet 65:491–502PubMed
107.
Papachristou C, Lin S (2006) A comparison of methods for intermediate fine mapping. Genet Epidemiol 30:677–689PubMed
108.
Atwood LD, Heard-Costa NL (2003) Limits of fine-mapping a quantitative trait. Genet Epidemiol 24:99–106PubMed
109.
Hsueh W-C, Goring HH, Blangero J, Mitchell BD (2001) Replication of linkage to quantitative trait loci: variation in location and magnitude of the LOD score. Genet Epidemiol 21(Suppl 1):S473–S478PubMed
110.
Roberts SB, MacLean CJ, Neale MC, Eaves LJ, Kendler KS (1999) Replication of linkage studies of complex traits: an examination of variation in location estimates. Am J Hum Genet 65:876–884PubMed
111.
Kruglyak L, Lander ES (1996) Limits on fine mapping of complex traits. Am J Hum Genet 58:1092–1093PubMed
112.
Hauser ER, Boehnke M, Guo SW, Risch N (1996) Affected-sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations. Genet Epidemiol 13:117–137PubMed
113.
Haiman CA, Patterson N, Freedman ML et al (2007) Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39:638–644PubMed
114.
American Diabetes Association (2008) Standards of medical care in diabetes 2008. Diabetes Care 31:S12–S54
115.
Lewis JP, Palmer ND, Hicks PJ et al (2008) Association analysis in African Americans of European-derived type 2 diabetes single nucleotide polymorphisms from whole-genome association studies. Diabetes 57:2220–2225PubMed
116.
Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517PubMed
117.
Florez JC, Hirschhorn J, Altshuler D (2003) The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu Rev Genom Hum Genet 4:257–291
118.
Hsueh W-C, Mitchell BD, Aburomia R et al (2000) Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study. Diabetes Care 23:595–601PubMed
119.
Shaw JT, Purdie DM, Neil HA, Levy JC, Turner RC (1999) The relative risks of hyperglycaemia, obesity and dyslipidaemia in the relatives of patients with type II diabetes mellitus. Diabetologia 42:24–27PubMed
120.
Weijnen CF, Rich SS, Meigs JB, Krolewski AS, Warram JH (2002) Risk of diabetes in siblings of index cases with type 2 diabetes: implications for genetic studies. Diabet Med 19:41–50PubMed
121.
Altshuler D, Daly MJ, Lander ES (2008) Genetic mapping in human disease. Science 322:881–888PubMed
122.
Holmkvist J, Almgren P, Lyssenko V et al (2008) Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes. Diabetes 57:1738–1744PubMed
123.
Wheeler DA, Srinivasan M, Egholm M et al (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452:872–876PubMed
124.
International HapMap C, Frazer KA, Ballinger DG et al (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861
125.
International HapMap C (2005) A haplotype map of the human genome. Nature 437:1299–1320
126.
Bellanne-Chantelot C, Carette C, Riveline J-P et al (2008) The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes 57:503–508PubMed
127.
Zondervan KT, Cardon LR (2004) The complex interplay among factors that influence allelic association. Nat Rev Genet 5:89–100PubMed
128.
Blangero J (2004) Localization and identification of human quantitative trait loci: king harvest has surely come. Curr Opin Genet Dev 14:233–240PubMed
129.
McCarthy MI, Abecasis GR, Cardon LR et al (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9:356–369PubMed
130.
Kidd JM, Cooper GM, Donahue WF et al (2008) Mapping and sequencing of structural variation from eight human genomes. Nature 453:56–64PubMed
131.
Donnelly P (2008) Progress and challenges in genome-wide association studies in humans. Nature 456:728–731PubMed
Metadata
Title
Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies
Authors
S. Lillioja
A. Wilton
Publication date
01-06-2009
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 6/2009
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-009-1324-9

Other articles of this Issue 6/2009

Diabetologia 6/2009 Go to the issue

Letter

Thiamine in diabetic nephropathy: a novel treatment modality? Reply to Alkhalaf A, Kleefstra N, Groenier KH et al. [letter]

Article

Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress

Short Communication

A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans

Article

Ambulatory blood pressure measurements are related to albumin excretion and are predictive for risk of microalbuminuria in young people with type 1 diabetes

Short Communication

Decreased levels of metabolic enzymes in pancreatic islets of patients with type 2 diabetes

Review

The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits