Lack of Association of the Ala45thr Neurod Polymorphism with Type 1 Diabetes Mellitus In

SUPPLEMENTARY INFORMATION

Appendix 1.1: D values for common polymorphisms identified by resequencing of NEUROD1 in 32 affected individuals

DIL Reference 4565 2402 4566 4567 4568 Number 4565 0.333 2402 0.906 0.659 4566 1.000 1.000 0.079 4567 0.848 0.692 1.000 0.923 4568 1.000 0.993 1.000 0.571 0.654

Appendix 1.2: r2 values for common polymorphisms identified by resequencing of NEUROD1 in 32 affected individuals

DIL Reference 4565 2402 4566 4567 4568 Number 4565 0.333 2402 0.722 0.659 4566 0.026 0.018 0.079 4567 0.025 0.019 1.000 0.923 4568 1.000 0.876 0.034 0.020 0.654

Appendix 1.3: Allele frequencies by population for common variants identified in NEUROD.  The Belfast and Yorkshire collection of families were analyzed as part of the UK population.

Parental Minor Allele Frequency in Population (%)

DIL Reference  USA Finland Norway Romania Number UK 4565 36.6 36.0 - - - 2402 36.8 36.8 36.4 37.3 36.9 4566 12.1 12.3 20.1 17.3 11.0 4567 13.6 11.9 - - - 4568 37.4 37.9 - - - Appendix 1.4: Data for transmission analysis by population for Ala45Thr / DIL2402 and DIL4566 by population.  The Belfast and Yorkshire collection of families were analyzed as part of the UK population. *Power is calculated for P < 0.05, OR of 1.2. Values in parentheses are values for OR of 1.5

Parental TDT GTRR *Power for *Power for Number of DIL Minor Allele 10% Minor 36% Minor Population Families Reference Frequency in Allele Allele Available Number Population Frequency Frequency T U PTDT PGTRR (%) (%) (%)

2402 36.8 410 401 0.76 0.78 UK 618 29.0 (90.6) 59.4 (99.9) 4566 12.1 198 184 0.51 0.8 2402 36.8 252 234 0.47 0.77 USA 328 17.6 (66.0) 36.0 (95.0) 4566 12.3 145 116 0.06 0.12 2402 36.4 506 505 0.98 0.49 Finland 926 40.7 (98.0) 76.8 (99.9) 4566 20.1 266 293 0.25 0.51 2402 37.3 145 162 0.32 0.34 Norway 159 10.9 (37.7) 19.9 (70.6) 4566 17.3 29 21 0.25 0.64 2402 36.9 119 138 0.24 0.18 Romania 233 13.8 (51.6) 27.1 (85.9) 4566 11.0 41 37 0.65 0.73

T = transmitted; U = untransmitted. Appendix 1.5

Inclusion Criteria for The British Diabetic Association – now Diabetes UK - Warren Repository – UK families (1):

 458 families.  Ascertained for at least two affected children in families where both parents are alive.  At least one child was diagnosed with type 1 diabetes before the age of 17 and the other under the age of 29 years at diagnosis.

Inclusion Criteria for Selected Human Biological Database Interchange (HBDI) – USA Families (2):

 328 families.  There are least two children affected with type 1 diabetes.  If there are more than two affected children, there is also at least one unaffected child in the family.  The proband was diagnosed with type 1 diabetes age 17 or younger and a second affected child was diagnosed with type 1 diabetes age 29 or under.

Inclusion Criteria for Belfast collection of families (3):

 250 families.  Families with at least one affected child and where both parents are alive.  Proband was diagnosed with type 1 diabetes before the age of 15.

Inclusion Criteria for Finnish collection of families (4):

 926 families.  Families with one or more child diagnosed with type 1 diabetes.  Insulin treatment at diagnosis or soon after (usually < 1 year).

Inclusion Criteria for Norwegian collection of families (5):

 159 families.  Families recruited as part of ENDIT study.  One child in the family clinically diagnosed as having type 1 diabetes at a pediatric department in a hospital in Norway.  Children were < 18 yr at age of onset.

Inclusion Criteria for Romanian collection of families (6):

 233 families.  Families with one or more child diagnosed with type 1 diabetes.  The child was on insulin treatment within one month from diagnosis and used insulin continuously following diagnosis.  No age of diagnosis limits were set but >80% of cases were diagnosed under the age of 18 yr.

Inclusion Criteria for the Yorkshire collection of families (Included with the UK collection in Appendix 1.3) (7):

 80 families.  Families must be resident within the former Yorkshire Regional Health Authority.  Families with children diagnosed with type 1 diabetes during 1993 and 1994.  Affected child diagnosed between the ages of 0 and 15 years of age. References

1. Bain SC, Todd JA, Barnett AH: The British Diabetic Association--Warren repository. Autoimmunity 7:83-85, 1990

2. Lernmark A: Human cell lines from families available for diabetes research. Diabetologia 34:61, 1991

3. Patterson CC, Carson DJ, Hadden DR, Waugh NR, Cole SK: A case-control investigation of perinatal risk factors for childhood IDDM in Northern Ireland and Scotland. Diabetes Care 17:376-381, 1994

4. Tuomilehto J, Lounamaa R, Tuomilehto-Wolf E, Reunanen A, Virtala E, Kaprio EA, Akerblom HK: Epidemiology of childhood diabetes mellitus in Finland--background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus. The Childhood Diabetes in Finland (DiMe) Study Group. Diabetologia 35:70-76, 1992

5. Undlien DE, Akselsen HE, Joner G, Dahl-Jorgensen K, Aagenaes O, Sovik O, Thorsby E, Ronningen KS: No difference in the parental origin of susceptibility HLA class II haplotypes among Norwegian patients with insulin-dependent diabetes mellitus. Am J Hum Genet 57:1511-1514, 1995

6. Ionescu-Tirgoviste C, Guja C, Herr M, Cucca E, Welsh K, Bunce M, Marshall S, Todd JA: Low frequency of HLA DRB1*03 - DQB1*02 and DQB1*0302 haplotypes in Romania is consistent with the country's low incidence of Type I diabetes. Diabetologia 44 Suppl 3:B60-66, 2001

7. Feltbower RG, McKinney PA, Parslow RC, Stephenson CR, Bodansky HJ: Type 1 diabetes in Yorkshire, UK: time trends in 0-14 and 15-29-year-olds, age at onset and age- period-cohort modelling. Diabet Med 20:437-441, 2003