22q11.2 microdeletion and increased risk for type 2 diabetes

Lily Van; Tracy Heung; Sarah L Malecki; Christian Fenn; Andrea Tyrer; Marcos Sanches; Eva W C Chow; Erik Boot; Maria Corral; Satya Dash; Susan R George; Anne S Bassett

doi:10.1016/j.eclinm.2020.100528

22q11.2 microdeletion and increased risk for type 2 diabetes

EClinicalMedicine. 2020 Sep 10:26:100528. doi: 10.1016/j.eclinm.2020.100528. eCollection 2020 Sep.

Authors

Lily Van^{1

2}, Tracy Heung^{1

3}, Sarah L Malecki^{1

4}, Christian Fenn^{1

5}, Andrea Tyrer^{1

5}, Marcos Sanches⁶, Eva W C Chow^{1

2}, Erik Boot^{1

3

7}, Maria Corral³, Satya Dash^{4

8

9}, Susan R George^{4

9

10}, Anne S Bassett^{1

2

3

11

12}

Affiliations

¹ Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
² Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
³ The Dalglish Family 22q Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
⁴ Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁵ Undergraduate Medical Education, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ Biostatistical Consulting Service, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
⁷ Advisium, 's Heeren Loo Zorggroep, Amersfoort, the Netherlands.
⁸ Banting & Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada.
⁹ Division of Endocrinology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
¹⁰ Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
¹¹ Toronto Congenital Cardiac Centre for Adults, and Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, Canada.
¹² Toronto General Research Institute and Campbell Family Mental Health Research Institute, Toronto, Ontario, Canada.

Abstract

Background: The 22q11.2 microdeletion is the pathogenic copy number variation (CNV) associated with 22q11.2 deletion syndrome (22q11.2DS, formerly known as DiGeorge syndrome). Familiar endocrinological manifestations include hypoparathyroidism and hypothyroidism, with recent elucidation of elevated risk for obesity in adults. In this study, we aimed to determine whether adults with 22q11.2DS have an increased risk of developing type 2 diabetes (T2D).

Methods: We studied the effect of the 22q11.2 microdeletion on risk for T2D, defined by history and glycosylated hemoglobin (HbA1c), using weighted survey data from the adult Canadian population (based on n = 11,874) and from a clinical cohort of adults with 22q11.2DS (n = 314), aged 17-69 years. Binomial logistic regression models accounted for age, sex, non-European ethnicity, family history of T2D, obesity, and antipsychotic medication use.

Findings: The 22q11.2 microdeletion was a significant independent risk factor for T2D (OR 2·44, 95% CI 1·39-4·31), accounting for other factors (p < 0·0001). All factors except sex were also significant within 22q11.2DS. The median age at diagnosis of T2D was significantly younger in 22q11.2DS than in the Canadian population sample (32 vs 50 years, p < 0·0001). In adults without T2D, HbA1c was significantly higher in 22q11.2DS than the population (p = 0·042), after accounting for younger age of the 22q11.2DS group.

Interpretation: The results support the 22q11.2 microdeletion as a novel independent risk factor and potential model for early onset T2D. The findings complement emerging evidence that rare CNVs may contribute to risk for T2D. The results have implications for precision medicine and research into the underlying pathogenesis of T2D.

Keywords: Diabetes; Early diagnosis; Genetics; Genotype; Molecular diagnostics; Risk; Structural variant.