Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11

Sergey Nejentsev; Luc J Smink; Deborah Smyth; Rebecca Bailey; Christopher E Lowe; Felicity Payne; Jennifer Masters; Lisa Godfrey; Alex Lam; Oliver Burren; Helen Stevens; Sarah Nutland; Neil M Walker; Anne Smith; Rebecca Twells; Bryan J Barratt; Charmain Wright; Lisa French; Yuan Chen; Panagiotis Deloukas; Jane Rogers; Ian Dunham; John A Todd

doi:https://doi.org/10.1186/1471-2156-8-24

Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11

Sergey Nejentsev, Luc J Smink, Deborah Smyth, Rebecca Bailey, Christopher E Lowe, Felicity Payne, Jennifer Masters, Lisa Godfrey, Alex Lam, Oliver Burren, Helen Stevens, Sarah Nutland, Neil M Walker, Anne Smith, Rebecca Twells, Bryan J Barratt, Charmain Wright, Lisa French, Yuan Chen, Panagiotis DeloukasJane Rogers, Ian Dunham, John A Todd

Research output: Contribution to journal › Article › Academic › peer-review

9 Citations (Scopus)

Abstract

BACKGROUND: In an effort to locate susceptibility genes for type 1 diabetes (T1D) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with T1D.

RESULTS: Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with T1D. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex T1D families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05 - 0.0026), located near the PAPD1 gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the T1D families. We also tested 13 polymorphisms in the PAPD1 gene and in five other loci in 1,612 T1D patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPD1 showed nominal evidence of association in both T1D families and in the case-control sample (P = 0.037 and 0.03, respectively).

CONCLUSION: We conclude that polymorphisms in the CREM and SDF1 genes have no major effect on T1D. The weak T1D association that we detected in the association scan near the PAPD1 gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.

Original language	English
Pages (from-to)	24
Journal	BMC genetics
Volume	8
DOIs	https://doi.org/10.1186/1471-2156-8-24
Publication status	Published - 17 May 2007
Externally published	Yes

Keywords

Case-Control Studies
Chromosomes, Human, Pair 10
DNA Primers
Diabetes Mellitus, Type 1/genetics
Female
Gene Frequency
Genetic Markers
Genotype
Humans
Male
Physical Chromosome Mapping
Polymorphism, Single Nucleotide

Access to Document

https://doi.org/10.1186/1471-2156-8-24

Cite this

Nejentsev, S., Smink, L. J., Smyth, D., Bailey, R., Lowe, C. E., Payne, F., Masters, J., Godfrey, L., Lam, A., Burren, O., Stevens, H., Nutland, S., Walker, N. M., Smith, A., Twells, R., Barratt, B. J., Wright, C., French, L., Chen, Y., ... Todd, J. A. (2007). Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11. BMC genetics, 8, 24. https://doi.org/10.1186/1471-2156-8-24

@article{3bb129a6c5d44c99a0067e345802a8a5,

title = "Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11",

abstract = "BACKGROUND: In an effort to locate susceptibility genes for type 1 diabetes (T1D) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with T1D.RESULTS: Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with T1D. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex T1D families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05 - 0.0026), located near the PAPD1 gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the T1D families. We also tested 13 polymorphisms in the PAPD1 gene and in five other loci in 1,612 T1D patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPD1 showed nominal evidence of association in both T1D families and in the case-control sample (P = 0.037 and 0.03, respectively).CONCLUSION: We conclude that polymorphisms in the CREM and SDF1 genes have no major effect on T1D. The weak T1D association that we detected in the association scan near the PAPD1 gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.",

keywords = "Case-Control Studies, Chromosomes, Human, Pair 10, DNA Primers, Diabetes Mellitus, Type 1/genetics, Female, Gene Frequency, Genetic Markers, Genotype, Humans, Male, Physical Chromosome Mapping, Polymorphism, Single Nucleotide",

author = "Sergey Nejentsev and Smink, {Luc J} and Deborah Smyth and Rebecca Bailey and Lowe, {Christopher E} and Felicity Payne and Jennifer Masters and Lisa Godfrey and Alex Lam and Oliver Burren and Helen Stevens and Sarah Nutland and Walker, {Neil M} and Anne Smith and Rebecca Twells and Barratt, {Bryan J} and Charmain Wright and Lisa French and Yuan Chen and Panagiotis Deloukas and Jane Rogers and Ian Dunham and Todd, {John A}",

year = "2007",

month = may,

day = "17",

doi = "https://doi.org/10.1186/1471-2156-8-24",

language = "English",

volume = "8",

pages = "24",

journal = "BMC genetics",

issn = "1471-2156",

publisher = "BioMed Central",

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Nejentsev, S, Smink, LJ, Smyth, D, Bailey, R, Lowe, CE, Payne, F, Masters, J, Godfrey, L, Lam, A, Burren, O, Stevens, H, Nutland, S, Walker, NM, Smith, A, Twells, R, Barratt, BJ, Wright, C, French, L, Chen, Y, Deloukas, P, Rogers, J, Dunham, I & Todd, JA 2007, 'Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11', BMC genetics, vol. 8, pp. 24. https://doi.org/10.1186/1471-2156-8-24

TY - JOUR

T1 - Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11

AU - Nejentsev, Sergey

AU - Smink, Luc J

AU - Smyth, Deborah

AU - Bailey, Rebecca

AU - Lowe, Christopher E

AU - Payne, Felicity

AU - Masters, Jennifer

AU - Godfrey, Lisa

AU - Lam, Alex

AU - Burren, Oliver

AU - Stevens, Helen

AU - Nutland, Sarah

AU - Walker, Neil M

AU - Smith, Anne

AU - Twells, Rebecca

AU - Barratt, Bryan J

AU - Wright, Charmain

AU - French, Lisa

AU - Chen, Yuan

AU - Deloukas, Panagiotis

AU - Rogers, Jane

AU - Dunham, Ian

AU - Todd, John A

PY - 2007/5/17

Y1 - 2007/5/17

N2 - BACKGROUND: In an effort to locate susceptibility genes for type 1 diabetes (T1D) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with T1D.RESULTS: Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with T1D. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex T1D families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05 - 0.0026), located near the PAPD1 gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the T1D families. We also tested 13 polymorphisms in the PAPD1 gene and in five other loci in 1,612 T1D patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPD1 showed nominal evidence of association in both T1D families and in the case-control sample (P = 0.037 and 0.03, respectively).CONCLUSION: We conclude that polymorphisms in the CREM and SDF1 genes have no major effect on T1D. The weak T1D association that we detected in the association scan near the PAPD1 gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.

AB - BACKGROUND: In an effort to locate susceptibility genes for type 1 diabetes (T1D) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with T1D.RESULTS: Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with T1D. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex T1D families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05 - 0.0026), located near the PAPD1 gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the T1D families. We also tested 13 polymorphisms in the PAPD1 gene and in five other loci in 1,612 T1D patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPD1 showed nominal evidence of association in both T1D families and in the case-control sample (P = 0.037 and 0.03, respectively).CONCLUSION: We conclude that polymorphisms in the CREM and SDF1 genes have no major effect on T1D. The weak T1D association that we detected in the association scan near the PAPD1 gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.

KW - Case-Control Studies

KW - Chromosomes, Human, Pair 10

KW - DNA Primers

KW - Diabetes Mellitus, Type 1/genetics

KW - Female

KW - Gene Frequency

KW - Genetic Markers

KW - Genotype

KW - Humans

KW - Male

KW - Physical Chromosome Mapping

KW - Polymorphism, Single Nucleotide

U2 - https://doi.org/10.1186/1471-2156-8-24

DO - https://doi.org/10.1186/1471-2156-8-24

M3 - Article

C2 - 17509149

SN - 1471-2156

VL - 8

SP - 24

JO - BMC genetics

JF - BMC genetics

ER -