A large set of Finnish affected sibling pair families with type 2 diabetes suggests susceptibility loci on chromosomes 6, 11, and 14.

The aim of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genes that predispose to type 2 diabetes or are responsible for variability in diabetes-related traits via a positional cloning and positional candidate gene approach. In a previously published genome-wide scan of 478 Finnish affected sibling pair (ASP) families (FUSION 1), the strongest linkage results were on chromosomes 20 and 11. We now report a second genome-wide scan using an independent set of 242 Finnish ASP families (FUSION 2), a detailed analysis of the combined set of 737 FUSION 1 + 2 families (495 updated FUSION 1 families), and fine mapping of the regions of chromosomes 11 and 20. The strongest FUSION 2 linkage results were on chromosomes 6 (maximum logarithm of odds score [MLS] = 2.30 at 95 cM) and 14 (MLS = 1.80 at 57 cM). For the combined FUSION 1 + 2 families, three results were particularly notable: chromosome 11 (MLS = 2.98 at 82 cM), chromosome 14 (MLS = 2.74 at 58 cM), and chromosome 6 (MLS = 2.66 at 96 cM). We obtained smaller FUSION 1 + 2 MLSs on chromosomes X (MLS = 1.27 at 152 cM) and 20p (MLS = 1.21 at 20 cM). Among the 10 regions that showed nominally significant evidence for linkage in FUSION 1, four (on chromosomes 6, 11, 14, and X) also showed evidence for linkage in FUSION 2 and stronger evidence for linkage in the combined FUSION 1 + 2 sample.

Chun Li | Kaisa Silander | Soumitra Ghosh | Michael P Epstein | Michael Boehnke | William Hagopian | Konstantinos N Lazaridis | Elizabeth R Hauser | Francis S Collins | Jaakko Tuomilehto | Tasha E Fingerlin | Julie A Douglas | Karen L Mohlke | Laura J Scott | Richard M Watanabe | Richard N Bergman | Kimberly F Doheny | Elizabeth W Pugh | F. Collins | M. Boehnke | R. Bergman | J. Douglas | M. Epstein | W. Hagopian | E. Hauser | K. Doheny | L. Scott | K. Mohlke | W. Duren | M. Erdos | H. Stringham | P. Chines | A. Jackson | N. Narisu | P. P. White | T. Buchanan | R. Watanabe | T. Valle | E. Pugh | J. Tuomilehto | K. Silander | Chun Xing Li | T. Fingerlin | Soumitra Ghosh | Narisu Narisu | K. Lazaridis | Anne U Jackson | Thomas A Buchanan | Michael R Erdos | Heather M Stringham | Timo T Valle | J. Hill | R. Porter | V. Magnuson | A. Unni | L. Segal | Peter Chines | Kerry R Wiles | K. Wiles | William L Duren | Peggy P White | Victoria L Magnuson | Kimberly Colby | Jason E Hill | Pablo Hollstein | Kathleen M Humphreys | Roshni A Kasad | Jessica Lambert | George Lin | Anabelle Morales-Mena | Kristin Patzkowski | Carrie Pfahl | Rachel Porter | David Rha | Leonid Segal | Yong D Suh | Jason Tovar | Arun Unni | Christian Welch | Yong D. Suh | Pablo E. Hollstein | Jason Tovar | A. Morales-Mena | C. Pfahl | George Lin | J. Lambert | R. A. Kasad | Kimberly Colby | Kristin Patzkowski | D. Rha | Christian Welch | R. Watanabe | Narisu Narisu | Anabelle Morales-Mena | C. Pfahl | Christian Welch | A. Jackson | Rachel Porter

[1]  Y. Chagnon,et al.  A genome-wide scan for abdominal fat assessed by computed tomography in the Québec Family Study. , 2001, Diabetes.

[2]  M. Boehnke,et al.  Genetic linkage analysis of complex genetic traits by using affected sibling pairs. , 1998, Biometrics.

[3]  P. Reynier,et al.  Cloning and initial characterization of human and mouse Spot 14 genes 1 , 1997, FEBS letters.

[4]  L. Peltonen,et al.  Genome-wide scan of obesity in Finnish sibpairs reveals linkage to chromosome Xq24. , 2000, The Journal of clinical endocrinology and metabolism.

[5]  R Foxon,et al.  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. , 2001, American journal of human genetics.

[6]  M P Epstein,et al.  Improved inference of relationship for pairs of individuals. , 2000, American journal of human genetics.

[7]  E McEwen,et al.  Translational control is required for the unfolded protein response and in vivo glucose homeostasis. , 2001, Molecular cell.

[8]  H M Stringham,et al.  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. , 2000, American journal of human genetics.

[9]  M. Luo,et al.  A genome-wide search for Type II diabetes susceptibility genes in Chinese Hans , 2001, Diabetologia.

[10]  M. Stern.  The search for type 2 diabetes susceptibility genes using whole‐genome scans: an epidemiologist's perspective , 2002, Diabetes/metabolism research and reviews.

[11]  J. Weber,et al.  Genomewide search for type 2 diabetes susceptibility genes in four American populations. , 2000, American journal of human genetics.

[12]  J. Michaud,et al.  Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. , 2001, Human molecular genetics.

[13]  Marybeth I. Maloney,et al.  “Spot 14” Protein Functions at the Pretranslational Level in the Regulation of Hepatic Metabolism by Thyroid Hormone and Glucose* , 1997, The Journal of Biological Chemistry.

[14]  L Kruglyak,et al.  Parametric and nonparametric linkage analysis: a unified multipoint approach. , 1996, American journal of human genetics.

[15]  Aravinda Chakravarti,et al.  Automated construction of genetic linkage maps using an expert system (MultiMap): a human genome linkage map , 1994, Nature Genetics.

[16]  S. Rich,et al.  Linkage of Genetic Markers on Human Chromosomes 20 and 12 to NIDDM in Caucasian Sib Pairs With a History of Diabetic Nephropathy , 1997, Diabetes.

[17]  J C Murray,et al.  Pediatrics and , 1998 .

[18]  Joseph B. Rayman,et al.  The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes. , 2000, American journal of human genetics.

[19]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[20]  C. Bogardus,et al.  A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. , 2000, The Journal of clinical investigation.

[21]  B. Zinman,et al.  Absence of association of type 2 diabetes with CAPN10 and PC-1 polymorphisms in Oji-Cree. , 2001, Diabetes care.

[22]  P. O'Connell,et al.  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. , 2001, American journal of human genetics.

[23]  J R O'Connell,et al.  PedCheck: a program for identification of genotype incompatibilities in linkage analysis. , 1998, American journal of human genetics.

[24]  Carl D Langefeld,et al.  Ordered subset analysis in genetic linkage mapping of complex traits , 2004, Genetic epidemiology.

[25]  Joseph B. Rayman,et al.  Methods for precise sizing, automated binning of alleles, and reduction of error rates in large-scale genotyping using fluorescently labeled dinucleotide markers. FUSION (Finland-U.S. Investigation of NIDDM Genetics) Study Group. , 1997, Genome research.

[26]  S. Zeger,et al.  Longitudinal data analysis using generalized linear models , 1986 .

[27]  F. Collins,et al.  Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H. Tsai,et al.  Type 2 diabetes and three calpain-10 gene polymorphisms in Samoans: no evidence of association. , 2001, American journal of human genetics.

[29]  H. Ogura,et al.  Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity , 1997, Nature.

[30]  S. Rich.  Genetic Epidemiological Perspective , 2006 .

[31]  G Scarlato,et al.  A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. , 1999, Diabetes.

[32]  C. Mariash,et al.  Direct Evidence for a Role of the "Spot 14" Protein in the Regulation of Lipid Synthesis (*) , 1995, The Journal of Biological Chemistry.

[33]  A. Whittemore,et al.  A class of tests for linkage using affected pedigree members. , 1994, Biometrics.

[34]  J. Beckmann,et al.  A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. , 1997, Human molecular genetics.

[35]  T. Matise,et al.  Erratum: Automated construction of genetic linkage maps using an expert system (MultiMap): A human genome linkage map (Nature Genetics (1994) 6 (384- 390)) , 1994 .

[36]  Veikko Salomaa,et al.  Prevalence of diabetes mellitus and impaired glucose tolerance in the middle-aged population of three areas in Finland. , 1991, International journal of epidemiology.

[37]  K Lange,et al.  A multipoint method for detecting genotyping errors and mutations in sibling-pair linkage data. , 2000, American journal of human genetics.

[38]  S. Lewitzky,et al.  A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population. , 2001, Diabetes.

[39]  R N Bergman,et al.  Mapping Genes for NIDDM: Design of the Finland—United States Investigation of NIDDM Genetics (FUSION) Study , 1998, Diabetes Care.

[40]  J. Stengård,et al.  Concordance for Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland , 1992, Diabetologia.

[41]  M. Boehnke,et al.  Accurate inference of relationships in sib-pair linkage studies. , 1997, American journal of human genetics.

[42]  Tom H. Lindner,et al.  Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus , 2000, Nature Genetics.

[43]  C. Dina,et al.  Genome-Wide Search for Type 2 Diabetes in Japanese Affected Sib-Pairs Confirms Susceptibility Genes on 3 q , 15 q , and 20 q and Identifies Two New Candidate Loci on 7 p and 11 p , 2002 .

[44]  A. Zinn,et al.  Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. , 2000, Human molecular genetics.

[45]  N J Cox,et al.  Allele-sharing models: LOD scores and accurate linkage tests. , 1997, American journal of human genetics.

[46]  Kaisa Silander,et al.  Variation in three single nucleotide polymorphisms in the calpain-10 gene not associated with type 2 diabetes in a large Finnish cohort. , 2002, Diabetes.

[47]  M. McCarthy,et al.  Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom. , 2001, American journal of human genetics.

[48]  C. Dina,et al.  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. , 2002, Diabetes.

[49]  S. Rich,et al.  New Susceptibility Locus for NIDDM Is Localized to Human Chromosome 20q , 1997, Diabetes.

[50]  S. Rich.  Mapping Genes in Diabetes: Genetic Epidemiological Perspective , 1990, Diabetes.