Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes

Dina Mansour Aly; Om Prakash Dwivedi; Rashmi B Prasad; Annemari Käräjämäki; Rebecka Hjort; Manonanthini Thangam; Mikael Åkerlund; Anubha Mahajan; Miriam S Udler; Jose C Florez; Mark I McCarthy; Julia Brosnan; Olle Melander; Sofia Carlsson; Ola Hansson; Tiinamaija Tuomi; Leif Groop; Emma Ahlqvist; Regeneron Genetics Center

doi:10.1038/s41588-021-00948-2

Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes

Dina Mansour Aly, Om Prakash Dwivedi, Rashmi B Prasad, Annemari Käräjämäki, Rebecka Hjort, Manonanthini Thangam, Mikael Åkerlund, Anubha Mahajan, Miriam S Udler, Jose C Florez, Mark I McCarthy, Julia Brosnan, Olle Melander, Sofia Carlsson, Ola Hansson, Tiinamaija Tuomi, Leif Groop, Emma Ahlqvist, Regeneron Genetics Center

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Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.

Originalspråk	engelska
Sidor (från-till)	1534-1542
Tidskrift	Nature Genetics
Volym	53
DOI	https://doi.org/10.1038/s41588-021-00948-2
Status	Published - 2021

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Ämnesklassifikation (UKÄ)

Endokrinologi och diabetes

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10.1038/s41588-021-00948-2

1 Doktorsavhandling (sammanläggning)

Genetics of Diabetes Subtypes. Characterization of novel cluster-based diabetes subtypes.
Mansour Aly, D., 2022, Lund: Lund University, Faculty of Medicine. 91 s.
Forskningsoutput: Avhandling › Doktorsavhandling (sammanläggning)

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Mansour Aly, D., Dwivedi, O. P., Prasad, R. B., Käräjämäki, A., Hjort, R., Thangam, M., Åkerlund, M., Mahajan, A., Udler, M. S., Florez, J. C., McCarthy, M. I., Brosnan, J., Melander, O., Carlsson, S., Hansson, O., Tuomi, T., Groop, L., Ahlqvist, E., & Regeneron Genetics Center (2021). Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes. Nature Genetics, 53, 1534-1542. https://doi.org/10.1038/s41588-021-00948-2

@article{6ed784f124f14a0d9b59ba9be7d1a5e1,

title = "Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes",

abstract = "Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.",

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author = "{Mansour Aly}, Dina and Dwivedi, {Om Prakash} and Prasad, {Rashmi B} and Annemari K{\"a}r{\"a}j{\"a}m{\"a}ki and Rebecka Hjort and Manonanthini Thangam and Mikael {\AA}kerlund and Anubha Mahajan and Udler, {Miriam S} and Florez, {Jose C} and McCarthy, {Mark I} and Julia Brosnan and Olle Melander and Sofia Carlsson and Ola Hansson and Tiinamaija Tuomi and Leif Groop and Emma Ahlqvist and {Regeneron Genetics Center}",

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Mansour Aly, D, Dwivedi, OP, Prasad, RB, Käräjämäki, A, Hjort, R, Thangam, M , Åkerlund, M, Mahajan, A, Udler, MS, Florez, JC, McCarthy, MI, Brosnan, J, Melander, O, Carlsson, S, Hansson, O, Tuomi, T, Groop, L, Ahlqvist, E & Regeneron Genetics Center 2021, 'Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes', Nature Genetics, vol. 53, s. 1534-1542. https://doi.org/10.1038/s41588-021-00948-2

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T1 - Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes

AU - Mansour Aly, Dina

AU - Dwivedi, Om Prakash

AU - Prasad, Rashmi B

AU - Käräjämäki, Annemari

AU - Hjort, Rebecka

AU - Thangam, Manonanthini

AU - Åkerlund, Mikael

AU - Mahajan, Anubha

AU - Udler, Miriam S

AU - Florez, Jose C

AU - McCarthy, Mark I

AU - Brosnan, Julia

AU - Melander, Olle

AU - Carlsson, Sofia

AU - Hansson, Ola

AU - Tuomi, Tiinamaija

AU - Groop, Leif

AU - Ahlqvist, Emma

AU - Regeneron Genetics Center

PY - 2021

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N2 - Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.

AB - Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.

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SN - 1546-1718

VL - 53

SP - 1534

EP - 1542

JO - Nature Genetics

JF - Nature Genetics

ER -

Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes

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Genetics of Diabetes Subtypes. Characterization of novel cluster-based diabetes subtypes.

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