Human Molecular Genetics

Figure 1. Multipoint maximum lod scores (MMLS) obtained in UK96 ([squ]), UK140 ([diamonds]), total 236 UK ([circle]) and US76 ([squf]) families. The markers are, from 10p11 to 10q11, D10S211-0.7-D10S582-2.1-GAD65/D10S197-0.3-D10S593
-0.4-D10S611-0.3-D10S600-0.3-D10S588-1.4-D10S1214
-0.9-D10S213-0.2-D10S601-0.2- D10S224-0.3- D10S204
-2.1-D10S193-0.5-D10S208/D10S183/D10S565/D10S199-1.5
-D10S675-2.6-D10S578-0.4-D10S176-2.6-D10S604-1.1-RBP3-2.0-D10S220-3.0-D10S539 (where `/' represents no observed recombination between markers). Intermarker distances were calculated from the 236 UK families and are in cM. GAD65 has been localized to 10p11.2 (9). The average percentage of IBD status information extracted at each marker from the 236 UK families was 98% (range 89-100%). The maternal recombination frequency within this map was ~6-fold greater than the paternal recombination frequency (data not shown). An extreme sex difference in recombination frequency extends from GAD₆₅ to D10S604 (maternal distance = 30.0 cM: paternal distance = 1.3 cM), in agreement with another genetic map of the region (16).

TDT analysis of microsatellite marker alleles

The evidence supporting linkage for the total 312 ASP families (P = 0.0007) could be expected to occur by chance at least once in a genome-wide search for polygenic disease susceptibility loci (17 ). However, the evidence of linkage exceeds that obtained from analysis of confirmed loci IDDM2, IDDM4, IDDM5 and IDDM8 in similar numbers of ASPs from the same populations (4 ; and data not shown). Therefore, the results warranted further study by using the TDT to test for linkage in the presence of allelic association in families (13 -15 ), which is a more sensitive approach to detecting and localizing susceptibility genes and can be done in families with only one affected child thereby extending the available data sets (4 ,18 -20 ). Initially, linkage by the TDT was assessed in the 236 UK ASP families because they were linked by ASP analysis to type 1 diabetes whereas the 76 US ASP families were not. To reduce the number of independent statistical tests and the potential for false positives only the common alleles (frequency >= 20% in parents) of those marker loci within the region of linkage with MMLS > 1.5 (P < 0.006) were analyzed. Because the candidate gene marker locus GAD₆₅ lay <1 cM distal of this region our analysis was extended to that marker. Table 1 shows TDT analysis in the total 236 UK families of the 17 marker loci in the region of linkage (a total of 28 alleles were tested). Allele 7 (298 bp) of D10S193 and allele 4 (142 bp) of D10S588 provided some evidence (P < 0.05) by the TDT for linkage with type 1 diabetes.

TDT and case control analysis of D10S193

Analysis of transmission from parents to type 1 diabetics of allele 7 of D10S193 was extended to an additional 142 UK ASP and simplex families, 185 US ASP families (including the 76 US ASP families previously tested by MMLS), 375 Norwegian, 167 Sardinian and 54 Italian simplex families. Non-diabetic siblings from these families, for which DNA was collected, were also analyzed. Table 2 a shows transmission of allele 7 of D10S193 from parents to diabetic and non-diabetic children. In all populations, transmission of allele 7 to diabetic children was >50%. However, only in the UK was the P value <0.05 (55% transmission; P = 0.01). When the data for all populations were combined the transmission was 54% [P = 0.006, and when corrected for the number of independent tests (Materials and Methods) P_c = 0.17]. To determine that transmission of the allele to diabetic children is dependent upon type 1 diabetes, and not owing to segregation distortion, we investigated transmission of allele 7 to non-diabetic children from the same type 1 diabetic families (Table 2 a) and to all available members of the 61 CEPH reference families. When the data for transmission to non affected children of all type 1 diabetic families were combined the transmission was 47%. A 2 * 2 test of heterogeneity provides evidence (P = 0.006, P_c = 0.17) that transmission of allele 7 to diabetic children is increased in comparison with non-diabetic children in type 1 diabetic families. Transmission of allele 7 to all available members of the 61 CEPH reference families exceeded non-transmission, but not significantly [274 transmissions (T) versus 235 non-transmissions (NT); 54%, P > 0.05]. A population based test for association of allele 7 of D10S193 to type 1 diabetes gave no independent evidence of linkage disequilibrium with type 1 diabetes (32, 100 and 98 patients with two, one or zero 298 bp alleles versus 52, 168 and 197 controls).

Table 1 . Transmission to diabetic children in 236 UK ASP families of the common alleles of microsatellite marker loci on chromosome 10p11

Marker	Allele	Frequency	Transmitted	Not transmitted	% transmitted	P
GAD65	5	22	115	119	49
	8	25	125	112	53
D10S197	5	20	124	146	46
	6	43	251	216	54
D10S593	12	55	182	154	54
D10S611	1	20	137	145	49
	2	30	184	204	47
	3	45	231	199	54
D10S600	10	26	182	175	51
	12	22	151	157	49
D10S588	4	68	233	189	55	0.03
D10S1214	NA	NA	NA	NA	NA
D10S213	14	31	202	164	55
D10S601	4	21	157	149	51
D10S224	5	32	187	181	51
	6	44	216	235	48
D10S204	3	35	227	198	53
D10S193	5	30	188	192	49
	7	32	229	187	55	0.04
D10S208	6	22	120	137	47
	7	35	153	176	47
	8	23	141	118	54
D10S183	14	22	149	129	54
D10S565	10	86	92	114	45
D10S199	4	23	146	168	46
	6	22	132	162	45
	7	26	185	154	55
D10S675	5	27	183	194	49
	9	47	233	227	51

Alleles are designated a rank by the PCR product size (1 = smallest). Only alleles >= 20% frequency in the parental population were included for analysis. A [chi]² test against the hypothesis of 50% transmission was used, only P values <0.05 are given. NA, no alleles were present at a frequency >= 20%.

Table 2 . (a) Percentage transmission of allele 7 of D10S193 to diabetic and non-diabetic children in UK, US, Norwegian, Sardinian and Italian families. Novel PCR primers were designed for this study, allele 7 (298 bp) is identical to the 225 bp allele amplified using the published Généthon primers (7). (b) Percentage transmission of allele 4 of D10S588 to diabetic and non-diabetic children in UK, US, Norwegian, Sardinian and Italian families

	UKP (n = 378)	US (n = 185)	Norwegian (n = 375)	Sardinian (n = 167)	Italian (n = 54)	Total (n = 1159)
(a) D10S193 (allele 7)
Diabetic	55	54	51	52	55	54
	(365:299)a	(174:151)	(134:127)	(51:48)	(12:10)	(736:635)b
Non-diabetic	48	51	47	45	44	47
	(58:64)	(24:23)	(155:175)	(38:47)	(12:15)	(287:324)
(b) D10S588 (allele 4)
Diabetic	55	57	51	49	38	54
	(344:286)a	(163:121)a	(137:130)	(59:62)	(12:20)	(715:619)b
Non-diabetic	57	66	55	52	61	56
	(74:56)	(46:24)b	(190:154)	(51:48)	(22:14)	(383:296)c

Number of transmissions versus number of non-transmissions are in brackets. A [chi]² test against the hypothesis of 50% transmission was used.^aP < 0.05; ^bP < 0.01; ^cP < 0.001.

Table 3 . Association of allele 4 of D10S588 in UK type 1 diabetic patients and controls

Allele/phenotype/genotype	Diabetics (n = 221)		Controls (n = 404)
Allele frequenciesa
4	312	71%	532	66%
X	130	29%	276	34%
Phenotype frequenciesa
4	199	90%	369	91%
X	22	10%	35	9%
Genotype frequenciesb
4/4	113	51%	163	40%
4/X	86	39%	206	51%
X/X	22	10%	35	9%

^a[chi]² test of heterogeneity P > 0.05; ^b[chi]² test of heterogeneity P = 0.01, odds ratio for 4/4 genotype = 1.5 (95% C.I. = 1.1-2.2; P = 0.009).

TDT and case control analysis of D10S588

We extended our analysis of the transmission of allele 4 of D10S588 to the same families used for the TDT study of D10S193. Table 2 b shows transmission from parents to diabetic and non-diabetic children, of allele 4 of D10S588 in the UK, US, Norwegian, Sardinian and Italian type 1 diabetic families. When the data for all populations were combined the transmission to diabetic children was increased (54%; P = 0.009, P_c = 0.25). However, transmission was only increased in the UK (55%; P = 0.02) and US (57%; P = 0.01) populations at P < 0.05. Surprisingly, transmission of allele 4 to non-diabetic children in type 1 diabetic families was >50% in all five populations. When the data for all populations were combined the transmission to non-diabetic children was 56% (P = 0.0008, P_c = 0.02). We tested transmission of allele 4 to all available members of the 61 CEPH reference families and found little deviation from the expected 50:50 (239T versus 242NT).

Association of allele 4 of D10S588 to type 1 diabetes was tested in an independent collection of UK Caucasian diabetics and controls. Table 3 shows some evidence that the allele 4 homozygous genotype confers increased risk to type 1 diabetes (odds ratio = 1.5; 95% C.I. = 1.1-2.2; P = 0.009).

DISCUSSION

Linkage to type 1 diabetes on human chromosome 10p11-q11 provides suggestive evidence for a susceptibility locus (IDDM10) in this region. Evidence of linkage in the presence of association at D10S193 and D10S588 extends this evidence. The type 1 diabetes locus on chromosome 10p11-q11 has provisionally been designated IDDM10.

The TDT is valid as a test of association but only when transmission is analysed to probands in multiplex families (15 ). Support for association in the 1159 families is not significant for allele 7 of D10S193 in the 1159 families [P_proband (Materials and Methods) = 0.057] but significant for allele 4 of D10S588 (P_proband = 0.021). Possible linkage disequilibrium of allele 4 of D10S588 with type 1 diabetes is also supported by the independent evidence of association of this allele in a case-control study. However, it has to be stressed that owing to population stratification effects arising from incorrectly matched controls, case-control results must be viewed with caution (21 ). The evidence is, however, complicated by the increased transmission of allele 4 to non-diabetic siblings of type 1 diabetics, whereas transmission in the CEPH reference families is at the expected level of 50%. Islet cell autoantibodies (ICA) are a predictor of type 1 diabetes in first-degree relatives of type 1 diabetic patients (22 ). It is possible that the observed positive transmission of allele 4 of D18S588 to non affected siblings in the diabetic families reflects transmission to those siblings that are positive for ICA or for other autoantibodies and insulitis, and that allele 4 is associated with a disease allele that predisposes to ICA development/insulitis and overt disease. This would be consistent with both the neutral transmission in the CEPH families and the evidence of association in the case control study. The ICA status of non affected siblings used in this study is unknown. Evidence for linkage of chromosome 2q34 with both type 1 diabetes and ICA positivity has been reported (23 ).

Given that the GAD₆₅ microsatellite and the very closely linked D10S197 microsatellite give no evidence of linkage by the TDT to type 1 diabetes a role for GAD₆₅ in genetic susceptibility is less likely, at least in the populations studied here. Furthermore, whilst transmission of the rare allele 8 of the GAD₆₅ microsatellite to diabetic children was increased in the study of Wapelhorst et al. (12 ) (54T versus 24NT), we found no significant increase in transmission of allele 8 to diabetic children (34T versus 30NT). Our results are in agreement with their conclusion that the GAD₆₅ gene does not play a significant role in genetic susceptibility to type 1 diabetes. Nevertheless, only a very high resolution linkage disequilibrium map of single nucleotide mutations including and surrounding the gene and regulatory region, in multiple populations, can comprehensively exclude a minor role for GAD₆₅ in susceptibility to type 1 diabetes.

Experience with type 1 diabetes indicates that identification of regions of linkage and/or linkage disequilibrium to polygenic disease is difficult. Investigations in one or two small populations are prone to false positives and are not sufficient to define a disease locus. In this study the chance of false positives was reduced by analysing a large number (1159) of type 1 diabetic families and minimizing the number of statistical tests [for example, by analyzing only frequent ( >= 20%) alleles]. Even so, >1159 families or families from more genetically isolated populations, and haplotypes of very closely linked markers from regions showing evidence of increased transmission of microsatellite alleles to affected children will have to be analysed to provide further evidence for the existence of a type 1 diabetes gene in the chromosome 10p11-q11 region.

MATERIALS AND METHODS

The 1159 type 1 diabetic families in this study are Caucasian with at least one diabetic child and both parents included. Where available DNA from non-diabetic siblings was obtained. The 378 UK families consisted of 24 simplex families collected from the Yorkshire region incorporating one diabetic diagnosed under age 17 years and one unaffected sibling, and 354 ASP families recruited as part of the British Diabetic Association-Warren repository. The total 185 US families were obtained from the Human Biological Database Interchange (HBDI). The UK96, UK140 and 76 US portions of the total ASP families, used for MMLS and TDT analyses, consisted of one diabetic diagnosed under age 17 years and the other under age 29. The additional 118 UK and 109 US ASP families, analyzed by TDT only, were not restricted by number of diabetic children nor age of diagnosis. The 375 Norwegian simplex families were comprised of one diabetic diagnosed under age 15 years and available non-diabetic siblings. The 167 Sardinian simplex families incorporated one diabetic diagnosed under age 17 years and at most one non-diabetic sibling. The 54 Italian type 1 diabetic families consisted of one diabetic child and available non-diabetic siblings. Unrelated UK diabetics and controls were as defined by Bain et al. (24 ). DNA from all available members of the total 61 CEPH reference families were used and the genotypes for marker loci D10S193 and D10S588 submitted to CEPH.

Microsatellite markers were identified from the public databases except for the GAD₆₅ locus microsatellite identified from Wapelhorst et al. (12 ). Fluorescence-based genotyping was undertaken using ABI 373A automated sequencers and associated genotyping software (Applied Biosystems) as previously described (25 ). Modifications were as follows. (i) PCRs were performed in 96-well microtitre plates (Costar) in a 10 [mu]l volume containing 0.2 U of AmpliTaq polymerase (Perkin-Elmer). (ii) Twenty-eight cycles (5 s at 95^oC, 30 s at 50-60^oC, 1 s at 72^oC) were performed in PTC-200 thermocyclers (MJ Research). (iii) Co-precipitation of PCR products was omitted and ~0.l [mu]l per marker was combined with the internal size standard and formamide. (iv) Single strand size markers GS-350 or GS-500 (Applied Biosystems) were used and three separate electrophoresis runs made with each gel. Raw allele sizes were allocated into bins and designated as population-specific alleles using the global adaptive binning facility of the Genome Analysis System software [GAS version 2.0: (c) A. Young, University of Oxford, 1993-1995] available on the internet at http://users.ox.ac.uk/~ayoung/gas.html.

The order of markers with the least total number of apparent recombinants was identified by the BESTORDER option of the SIBMAP analysis routine in GAS and used in conjunction with the Whitehead institute/MIT human physical mapping project database (http://www-genome.wi.mit.edu) to produce the order of markers shown in Figure 1 . The inter-marker recombination fractions were calculated by GAS. Distances <0.5 cM are based on one or zero recombinants and are therefore not accurate. This rapid method of linkage mapping provides a rudimentary map of very closely linked markers for which only a detailed physical map will identify the exact marker order and inter-marker distance. Novel primers were designed for marker loci D10S213, D10S193, D10S183, D10S199, D10S578, D10S604, D10S220 and D10S539. Primer sequences and allele frequencies for all markers are available on the internet at http://www.well.ox.ac.uk.

Multipoint maximum lod scores (MMLS), Z₀ values and informativity across the region were calculated with the MAPMAKER/SIBS program (26 ). The P values assigned to MMLS scores are theoretical (27 ).

The transmission disequilibrium test (TDT) (13 -15 ) was undertaken using the ASSTDT analysis routine in GAS. Allelic transmissions from heterozygous parents to all children in each family are included. The test statistic (the `TDT') is a [chi]² (1df) statistic, which tests deviation of transmission from the expected 50% transmission of an allele from heterozygous parents to offspring. TDT P values are reported uncorrected (P) and corrected (P_c) for the multiple tests done initially (P values were multiplied by 28, to account for the 28 microsatellite marker alleles initially tested by the TDT). Extent of linkage disequilibrium of a marker allele with disease was quantitated by percent transmission which is the number of times an allele is transmitted from heterozygous parents to affected children divided by the total number of transmissions, expressed as a percentage. The TDT was also used as a test of association by testing transmission to probands only (15 ) (P_proband).

ACKNOWLEDGEMENTS

We gratefully acknowledge the blood donations from patients, their families and other individuals and thank Alan Young, June Davies, Zeinat Atta, Jackie Carr-Smith, Carolyn Smyth and Beth Rowe for their contributions to this study, and the Human Biological Data Interchange, the British Diabetic Association (BDA) and CEPH for US and UK and reference families. This work was supported financially by the Wellcome Trust, the BDA, the Norwegian Diabetes Association, the UK Medical Research Council, Lilly Industries UK and the Juvenile Diabetes Foundation International (JDFI). P.W.R. was a Wellcome Trust Prize Student, T.R.M. was a Wellcome Trust-New Zealand Health Research Council Overseas Postdoctoral Fellow and is currently a JDFI Postdoctoral Fellow and J.A.T. is a Wellcome Trust Principal Research Fellow.

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*To whom correspondence should be addressed. Tel: +44 1865 740014; Fax: +44 1865 742193; Email: john.todd{at}well.ox.ac.uk
⁺Present address: Gemini Research Ltd, 162 Science Park, Milton Road, Cambridge CB4 4GH, UK

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