Causal relationship between type 2 diabetes mellitus and cognitive impairment based on Mendelian randomization

doi:10.3969/j.issn.1674-8115.2025.02.009

Abstract

Abstract:

Objective ·To investigate the causal relationship between type 2 diabetes mellitus (T2DM) and cognitive dysfunction using two-sample Mendelian randomisation (MR). Methods ·Instrumental variables associated with T2DM were pooled from a large-scale genome-wide association study (GWAS) dataset. Inverse variance weighting was used as the primary analytical technique, supplemented by MR-Egger regression, weighted median and simple median analyses. Meta-analysis was jointly applied to combine different endpoints and to analyse the possibility of a causal relationship between T2DM and dementia, Alzheimer's disease, and Parkinson's dementia. Horizontal pleiotropy was examined by MR-PRESSO global test and MR-Egger analysis. Results ·There was a causal relationship between genetically predicted T2DM and dementia (OR=1.11, 95%CI 1.02~1.20, P=1.96×10^-2) and AD (OR=1.16, 95%CI 1.04~1.30, P=8.41×10^-3). Meta-analysis also supported the association between T2DM and cognitive impairment (OR=1.12, 95%CI 1.05~1.20, P=4.22×10^-4). A series of sensitivity analyses suggested the absence of heterogeneity and horizontal pleiotropy. Reverse MR analysis showed no significant causal relationship of various types of dementia on T2DM. Conclusion ·T2DM is positively associated with the risk of developing various types of dementia, suggesting that T2DM may be an important risk factor for cognitive impairment.

Key words: type 2 diabetes mellitus, cognitive dysfunction, Mendelian randomisation study

CLC Number:

R587.1

LIN Yijia, CHENG Lizhen, HU Tingjun, MIAO Ya. Causal relationship between type 2 diabetes mellitus and cognitive impairment based on Mendelian randomization[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 204-210.

Figures/Tables 5

TrendMD

References 33

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Phenotype	Sample size/n	Cases/n	Controls/n	Diagnostic criteria	Population
T2DM	298 957	48 298	250 671	Literature[12]	European
Dementia	216 771	7 284	209 487	ICD-10: F00-F09	European
AD	218 792	3 899	214 893	ICD-10: G30	European
PD	216 895	267	216 628	ICD-10: F02.3	European

Phenotype	Sample size/n	Cases/n	Controls/n	Diagnostic criteria	Population
T2DM	298 957	48 298	250 671	Literature[12]	European
Dementia	216 771	7 284	209 487	ICD-10: F00-F09	European
AD	218 792	3 899	214 893	ICD-10: G30	European
PD	216 895	267	216 628	ICD-10: F02.3	European

SNP	Beta	SE	P value	R²/%	F
rs730497	0.041 3	0.008 4	3.07×10^-8	0.05	24.17
rs13133548	0.033 4	0.006 6	5.00×10^-8	0.06	25.61
rs9388489	0.034 5	0.006 7	1.19×10^-8	0.06	26.51
rs10906115	-0.033 9	0.006 3	4.96×10^-8	0.05	28.95
rs1077394	0.036 9	0.006 8	3.92×10^-8	0.06	29.45
rs4812831	0.058 7	0.010 0	1.32×10^-8	0.08	34.46
rs16826069	0.046 5	0.007 9	6.97×10^-9	0.07	34.65
rs11063069	0.046 9	0.007 8	3.44×10^-10	0.07	36.15
rs4607103	-0.041 5	0.006 9	6.76×10^-10	0.07	36.17
rs55834942	-0.051 4	0.008 5	1.35×10^-12	0.07	36.57
rs738409	0.044 7	0.007 3	2.77×10^-11	0.07	37.49
rs4502156	-0.040 0	0.006 5	9.55×10^-11	0.08	37.87
rs6905288	0.040 1	0.006 5	5.77×10^-11	0.08	38.06
rs243021	0.040 2	0.006 5	4.60×10^-11	0.05	38.25
rs4457053	-0.046 6	0.007 5	3.68×10^-13	0.08	38.61
rs8042680	0.042 7	0.006 8	1.66×10^-10	0.09	39.43
rs10758593	0.039 3	0.006 2	2.56×10^-11	0.08	40.18
rs2796441	--0.040 0	0.006 3	4.86×10^-11	0.08	40.31
rs6813195	-0.046 1	0.007 0	1.53×10^-12	0.09	43.37
rs731839	-0.044 3	0.006 7	7.42×10^-13	0.09	43.72
rs972283	0.047 3	0.007 0	1.51×10^-12	0.11	45.66
rs1558902	0.046 1	0.006 7	2.13×10^-10	0.10	47.34
rs1531343	0.067 5	0.009 8	2.36×10^-14	0.10	47.44
rs35720761	-0.072 1	0.010 4	8.31×10^-16	0.10	48.06
rs28265	-0.088 5	0.012 6	4.45×10^-14	0.38	49.33
rs10842994	-0.057 5	0.008 1	7.60×10^-13	0.10	50.39
rs58542926	0.083 6	0.011 6	3.36×10^-15	0.10	51.94
rs7202877	-0.072 6	0.009 9	3.14×10^-14	0.10	53.78
rs7177055	0.052 8	0.007 2	5.65×10^-14	0.13	53.78
rs9379084	-0.094 6	0.012 9	1.47×10^-17	0.18	53.78
rs459193	0.053 7	0.007 2	6.71×10^-15	0.12	55.63
rs8108269	0.054 3	0.007 2	5.15×10^-16	0.13	56.88
rs340874	0.048 6	0.006 3	1.41×10^-15	0.10	59.51
rs10244051	0.047 9	0.006 2	7.87×10^-18	0.11	59.69
rs60980157	-0.061 5	0.007 9	6.63×10^-16	0.14	60.60
rs1359790	-0.058 5	0.007 3	1.34×10^-15	0.13	64.22
rs1801282	-0.091 6	0.011 0	2.68×10^-19	0.17	69.34
rs1260326	0.054 3	0.006 5	3.18×10^-18	0.14	69.79
rs516946	0.065 2	0.007 6	9.32×10^-20	0.15	73.60
rs1801212	0.063 0	0.007 3	7.09×10^-21	0.15	74.48
rs2943641	0.060 3	0.006 9	1.43×10^-18	0.05	76.37
rs12571751	-0.055 9	0.006 2	3.14×10^-22	0.16	81.29
rs5219	-0.063 0	0.006 5	1.52×10^-22	0.18	93.94
rs7501939	-0.062 2	0.006 4	2.38×10^-24	0.18	94.45
rs11603334	-0.088 1	0.009 0	1.72×10^-24	0.20	95.82
rs13389219	-0.071 5	0.007 0	1.32×10^-29	0.24	104.33
rs11708067	-0.083 9	0.007 8	9.32×10^-31	0.23	115.70
rs864745	-0.070 1	0.006 5	2.87×10^-30	0.24	116.31
rs5015480	-0.070 9	0.006 5	1.36×10^-30	0.25	118.98
rs10830963	0.082 9	0.007 2	9.44×10^-30	0.28	132.57
rs2237895	0.079 7	0.006 6	1.83×10^-38	0.31	145.82
rs13266634	-0.089 7	0.006 8	1.30×10^-47	0.34	174.01
rs4402960	0.091 9	0.006 6	8.31×10^-49	0.38	193.88
rs10965250	-0.129 8	0.009 3	3.71×10^-46	0.07	194.80
rs7756992	0.107 3	0.006 7	1.33×10^-61	0.09	256.48
rs7903146	0.241 0	0.006 9	1.00×10^-200	0.41	1 219.93

SNP	Beta	SE	P value	R²/%	F
rs730497	0.041 3	0.008 4	3.07×10^-8	0.05	24.17
rs13133548	0.033 4	0.006 6	5.00×10^-8	0.06	25.61
rs9388489	0.034 5	0.006 7	1.19×10^-8	0.06	26.51
rs10906115	-0.033 9	0.006 3	4.96×10^-8	0.05	28.95
rs1077394	0.036 9	0.006 8	3.92×10^-8	0.06	29.45
rs4812831	0.058 7	0.010 0	1.32×10^-8	0.08	34.46
rs16826069	0.046 5	0.007 9	6.97×10^-9	0.07	34.65
rs11063069	0.046 9	0.007 8	3.44×10^-10	0.07	36.15
rs4607103	-0.041 5	0.006 9	6.76×10^-10	0.07	36.17
rs55834942	-0.051 4	0.008 5	1.35×10^-12	0.07	36.57
rs738409	0.044 7	0.007 3	2.77×10^-11	0.07	37.49
rs4502156	-0.040 0	0.006 5	9.55×10^-11	0.08	37.87
rs6905288	0.040 1	0.006 5	5.77×10^-11	0.08	38.06
rs243021	0.040 2	0.006 5	4.60×10^-11	0.05	38.25
rs4457053	-0.046 6	0.007 5	3.68×10^-13	0.08	38.61
rs8042680	0.042 7	0.006 8	1.66×10^-10	0.09	39.43
rs10758593	0.039 3	0.006 2	2.56×10^-11	0.08	40.18
rs2796441	--0.040 0	0.006 3	4.86×10^-11	0.08	40.31
rs6813195	-0.046 1	0.007 0	1.53×10^-12	0.09	43.37
rs731839	-0.044 3	0.006 7	7.42×10^-13	0.09	43.72
rs972283	0.047 3	0.007 0	1.51×10^-12	0.11	45.66
rs1558902	0.046 1	0.006 7	2.13×10^-10	0.10	47.34
rs1531343	0.067 5	0.009 8	2.36×10^-14	0.10	47.44
rs35720761	-0.072 1	0.010 4	8.31×10^-16	0.10	48.06
rs28265	-0.088 5	0.012 6	4.45×10^-14	0.38	49.33
rs10842994	-0.057 5	0.008 1	7.60×10^-13	0.10	50.39
rs58542926	0.083 6	0.011 6	3.36×10^-15	0.10	51.94
rs7202877	-0.072 6	0.009 9	3.14×10^-14	0.10	53.78
rs7177055	0.052 8	0.007 2	5.65×10^-14	0.13	53.78
rs9379084	-0.094 6	0.012 9	1.47×10^-17	0.18	53.78
rs459193	0.053 7	0.007 2	6.71×10^-15	0.12	55.63
rs8108269	0.054 3	0.007 2	5.15×10^-16	0.13	56.88
rs340874	0.048 6	0.006 3	1.41×10^-15	0.10	59.51
rs10244051	0.047 9	0.006 2	7.87×10^-18	0.11	59.69
rs60980157	-0.061 5	0.007 9	6.63×10^-16	0.14	60.60
rs1359790	-0.058 5	0.007 3	1.34×10^-15	0.13	64.22
rs1801282	-0.091 6	0.011 0	2.68×10^-19	0.17	69.34
rs1260326	0.054 3	0.006 5	3.18×10^-18	0.14	69.79
rs516946	0.065 2	0.007 6	9.32×10^-20	0.15	73.60
rs1801212	0.063 0	0.007 3	7.09×10^-21	0.15	74.48
rs2943641	0.060 3	0.006 9	1.43×10^-18	0.05	76.37
rs12571751	-0.055 9	0.006 2	3.14×10^-22	0.16	81.29
rs5219	-0.063 0	0.006 5	1.52×10^-22	0.18	93.94
rs7501939	-0.062 2	0.006 4	2.38×10^-24	0.18	94.45
rs11603334	-0.088 1	0.009 0	1.72×10^-24	0.20	95.82
rs13389219	-0.071 5	0.007 0	1.32×10^-29	0.24	104.33
rs11708067	-0.083 9	0.007 8	9.32×10^-31	0.23	115.70
rs864745	-0.070 1	0.006 5	2.87×10^-30	0.24	116.31
rs5015480	-0.070 9	0.006 5	1.36×10^-30	0.25	118.98
rs10830963	0.082 9	0.007 2	9.44×10^-30	0.28	132.57
rs2237895	0.079 7	0.006 6	1.83×10^-38	0.31	145.82
rs13266634	-0.089 7	0.006 8	1.30×10^-47	0.34	174.01
rs4402960	0.091 9	0.006 6	8.31×10^-49	0.38	193.88
rs10965250	-0.129 8	0.009 3	3.71×10^-46	0.07	194.80
rs7756992	0.107 3	0.006 7	1.33×10^-61	0.09	256.48
rs7903146	0.241 0	0.006 9	1.00×10^-200	0.41	1 219.93

Outcome	Heterogeneity		Pleiotropy
Outcome	IVW Cochran's Q P value	MR-Egger Cochran's Q P value	MR-Egger intercept P value	MR-PRESSO global test P value
Dementia	0.115	0.125	0.247	0.136
AD	0.656	0.633	0.548	0.639
PD	0.382	0.346	0.922	0.368