Genome-Wide Association Study on the Early-Phase Insulin Response to a Liquid Mixed Meal: Results From the NEO Study

Genetics/Genomes/Proteomics/Metabolomics

¹Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
²Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
³University Medical Center Utrecht, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands
⁴Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
⁵Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
⁶Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
⁷Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
⁸Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands

Diabetes 2019 Dec; 68(12): 2327-2336. https://doi.org/10.2337/db19-0378

Article Figures & Tables

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Figure 1
Manhattan plot for the GWAS on Δinsulin, ln(insulin30) − ln(insulin0), in the discovery cohort (n = 3,518).
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Figure 2
The associations between T2D-associated SNPs (N = 143) and Δinsulin, ln(insulin30) − ln(insulin0), in the entire NEO cohort (N = 4,751).
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Figure 3
The distributions of natural logarithm–transformed insulin response across different ABO blood groups in the NEO study.

Table 1

Characteristics of the discovery and replication cohort from the NEO study

Characteristics	Insulin₃₀		ΔInsulin		IGI		IR_BMIadj
Characteristics	Discovery	Replication	Discovery	Replication	Discovery	Replication	Discovery	Replication
N	3,526	1,239	3,518	1,233	3,441	1,202	3,503	1,228
Age (years)	56 (51, 61)	56 (51, 61)	56 (51, 61)	56 (51, 61)	56 (51, 61)	56 (51, 61)	56 (51, 61)	56 (51, 61)
Women, N (%)	1,757 (50.0)	678 (54.7)	1,753 (49.8)	674 (54.7)	1,701 (49.4)	654 (54.4)	1,743 (49.8)	669 (54.5)
BMI (kg/m²)	30.1 (28.3, 32.6)	25.5 (23.2, 27.9)	30.1 (28.3, 32.6)	25.5 (23.3, 27.9)	30.1 (28.3, 32.6)	25.5 (23.2, 27.9)	30.1 (28.3, 32.6)	25.5 (23.2, 27.9)
Fasting serum measures
Glucose (mmol/L)	5.5 (5.2, 5.9)	5.3 (5.0, 5.6)	5.5 (5.2, 5.9)	5.3 (5.0, 5.6)	5.5 (5.2, 5.9)	5.3 (5.0, 5.6)	5.5 (5.2, 5.9)	5.3 (5.0, 5.6)
Insulin (mU/L)	10.9 (7.5, 15.7)	7.8 (5.2, 11.7)	10.9 (7.5, 15.7)	7.8 (5.2, 11.7)	10.8 (7.4, 15.6)	7.7 (5.2, 11.7)	10.9 (7.5, 15.7)	7.8 (5.2, 11.7)
HbA_1c (%)	5.3 (5.2, 5.5)	5.3 (5.1, 5.4)	5.3 (5.2, 5.5)	5.3 (5.1, 5.4)	5.3 (5.2, 5.5)	5.3 (5.1, 5.4)	5.3 (5.2, 5.5)	5.3 (5.1, 5.4)
Serum measures at 30 min
Glucose (mmol/L)	7.1 (6.2, 8.1)	6.2 (5.3, 7.2)	7.1 (6.2, 8.1)	6.2 (5.3, 7.2)	7.1 (6.2, 8.1)	6.2 (5.3, 7.2)	7.1 (6.2, 8.1)	6.2 (5.3, 7.2)
Insulin (mU/L)	61.4 (42.8, 89.6)	49.1 (34.9, 69.1)	61.3 (42.7, 89.6)	49.1 (34.9, 69.0)	61.3 (42.8, 89.4)	48.8 (34.6, 68.9)	61.4 (42.8, 89.6)	49.1 (34.8, 69.1)

Results are presented as median (interquartile range) unless otherwise indicated.

Table 2

Independent lead SNPs that reached genome-wide significance under four different measures of early-phase insulin response

Chr	SNP	Phenotype	Position	Location	Gene	Effect/noneffect allele	Effect allele frequency^a	Imputation quality^a	Discovery cohort			Replication cohort
Chr	SNP	Phenotype	Position	Location	Gene	Effect/noneffect allele	Effect allele frequency^a	Imputation quality^a	Effect size per allele (%)^b	SE	P	Effect size per allele (%)^b	SE	P
3	rs115404340	insulin₃₀	67839179	Intron	SUCLG2-AS1	G/A	0.01	0.44	78.5	0.098	3.8E-9	−15.7	0.13	0.19
9	rs505922	ΔInsulin	136149229	Intron	ABO	C/T	0.32	1	−6.5	0.012	3.3E-8	−7.8	0.021	7.2E-5^*
9	rs657152	IGI	136139265	Intron	ABO	A/C	0.34	0.98	8.1	0.011	3.0E-12	2.7	0.017	0.11
19	rs74889068	IGI	46199363	Intron	QPCTL	A/G	0.15	0.93	−8.8	0.016	3.8E-9	−2.1	0.024	0.36
3	rs115404340	IR_BMIadj	67839179	Intron	SUCLG2-AS1	G/A	0.01	0.42	72.5	0.092	3.4E-9	−9.8	0.12	0.41
19	rs74889068	IR_BMIadj	46199363	Intron	QPCTL	A/G	0.15	0.93	−10.9	0.018	4.4E-11	−4.0	0.028	0.14

Threshold for genome-wide significance is 5 × 10⁻⁸. Chr, chromosome.
* A successful replication, with P value < 0.05.
a In the discovery cohort.
b β-Coefficient expressed as the percentage difference in the outcome by one copy of the effect allele.