Neurocognitive impairment in type 2 diabetes: evidence for shared genetic aetiology

Josephine Mollon; Joanne E Curran; Samuel R Mathias; Emma E M Knowles; Phoebe Carlisle; Peter T Fox; Rene L Olvera; Harald H H Göring; Amanda Rodrigue; Laura Almasy; Ravi Duggirala; John Blangero; David C Glahn

doi:10.1007/s00125-020-05101-y

Neurocognitive impairment in type 2 diabetes: evidence for shared genetic aetiology

Diabetologia. 2020 May;63(5):977-986. doi: 10.1007/s00125-020-05101-y. Epub 2020 Feb 4.

Authors

Josephine Mollon¹, Joanne E Curran^{2

3}, Samuel R Mathias⁴, Emma E M Knowles⁴, Phoebe Carlisle⁵, Peter T Fox⁶, Rene L Olvera^{6

7}, Harald H H Göring^{2

3}, Amanda Rodrigue⁴, Laura Almasy⁸, Ravi Duggirala^{2

3}, John Blangero^{2

3}, David C Glahn^{4

5}

Affiliations

¹ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, 1 Autumn Street, BCH 3428, Boston, MA, 02115, USA. josephine.mollon@childrens.harvard.edu.
² Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA.
³ South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA.
⁴ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, 1 Autumn Street, BCH 3428, Boston, MA, 02115, USA.
⁵ Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA.
⁶ Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁷ Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁸ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Abstract

Aims/hypothesis: Type 2 diabetes is associated with cognitive impairments, but it is unclear whether common genetic factors influence both type 2 diabetes risk and cognition.

Methods: Using data from 1892 Mexican-American individuals from extended pedigrees, including 402 with type 2 diabetes, we examined possible pleiotropy between type 2 diabetes and cognitive functioning, as measured by a comprehensive neuropsychological test battery.

Results: Negative phenotypic correlations (ρ_p) were observed between type 2 diabetes and measures of attention (Continuous Performance Test [CPT d']: ρ_p = -0.143, p = 0.001), verbal memory (California Verbal Learning Test [CVLT] recall: ρ_p = -0.111, p = 0.004) and face memory (Penn Face Memory Test [PFMT]: ρ_p = -0.127, p = 0.002; PFMT Delayed: ρ_p = -0.148, p = 2 × 10^-4), replicating findings of cognitive impairment in type 2 diabetes. Negative genetic correlations (ρ_g) were also observed between type 2 diabetes and measures of attention (CPT d': ρ_g = -0.401, p = 0.001), working memory (digit span backward test: ρ_g = -0.380, p = 0.005), and face memory (PFMT: ρ_g = -0.476, p = 2 × 10^-4; PFMT Delayed: ρ_g = -0.376, p = 0.005), suggesting that the same genetic factors underlying risk for type 2 diabetes also influence poor cognitive performance in these domains. Performance in these domains was also associated with type 2 diabetes risk using an endophenotype ranking value approach. Specifically, on measures of attention (CPT d': β = -0.219, p = 0.005), working memory (digit span backward: β = -0.326, p = 0.035), and face memory (PFMT: β = -0.171, p = 0.023; PFMT Delayed: β = -0.215, p = 0.005), individuals with type 2 diabetes showed the lowest performance, while unaffected/unrelated individuals showed the highest performance, and those related to an individual with type 2 diabetes performed at an intermediate level.

Conclusions/interpretation: These findings suggest that cognitive impairment may be a useful endophenotype of type 2 diabetes and, therefore, help to elucidate the pathophysiological underpinnings of this chronic disease.

Data availability: The data analysed in this study is available in dbGaP: www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001215.v2.p2.

Keywords: Cognitive function; Cognitive impairment; Genetic correlation; Genetic overlap; Type 2 diabetes.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Cognition / physiology
Cognition Disorders / genetics
Cognition Disorders / physiopathology
Cognitive Dysfunction / genetics
Cognitive Dysfunction / physiopathology
Diabetes Mellitus, Type 2 / genetics*
Diabetes Mellitus, Type 2 / physiopathology*
Female
Humans
Male
Memory, Short-Term / physiology
Middle Aged
Neuropsychological Tests
Young Adult

Abstract

Publication types

MeSH terms

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