Sixty-Five Common Genetic Variants and Prediction of Type 2 Diabetes

Philippa J. Talmud; Jackie A. Cooper; Richard W. Morris; Frank Dudbridge; Tina Shah; Jorgen Engmann; Caroline Dale; Jon White; Stela McLachlan; Delilah Zabaneh; Andrew Wong; Ken K. Ong; Tom Gaunt; Michael V. Holmes; Debbie A. Lawlor; Marcus Richards; Rebecca Hardy; Diana Kuh; Nicholas Wareham; Claudia Langenberg; Yoav Ben-Shlomo; S. Goya Wannamethee; Mark W.J. Strachan; Meena Kumari; John C. Whittaker; Fotios Drenos; Mika Kivimaki; Aroon D. Hingorani; Jacqueline F. Price; Steve E. Humphries

doi:10.2337/db14-1504

Genetics/Genomes/Proteomics/Metabolomics

Sixty-Five Common Genetic Variants and Prediction of Type 2 Diabetes

Philippa J. Talmud¹ ⇑,
Jackie A. Cooper¹,
Richard W. Morris²,
Frank Dudbridge³,
Tina Shah⁴,
Jorgen Engmann⁴,
Caroline Dale³,
Jon White⁵,
Stela McLachlan⁶,
Delilah Zabaneh⁵,
Andrew Wong⁷,
Ken K. Ong⁷,⁸,
Tom Gaunt⁹,¹⁰,
Michael V. Holmes⁴,¹¹,
Debbie A. Lawlor⁹,¹⁰,
Marcus Richards⁷,
Rebecca Hardy⁷,
Diana Kuh⁷,
Nicholas Wareham⁸,
Claudia Langenberg⁴,⁸,
Yoav Ben-Shlomo¹⁰,
S. Goya Wannamethee²,
Mark W.J. Strachan¹²,
Meena Kumari⁴,
John C. Whittaker¹³,
Fotios Drenos¹,¹⁰,
Mika Kivimaki⁴,
Aroon D. Hingorani⁴,¹⁴,
Jacqueline F. Price⁶ and
Steve E. Humphries¹
on behalf of the UCLEB Consortium

¹Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, U.K.
²Department of Primary Care and Population Health, University College London, Royal Free Campus, London, U.K.
³Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, U.K.
⁴Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K.
⁵University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, U.K.
⁶Centre for Population Health Sciences, University of Edinburgh, Edinburgh, U.K.
⁷Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, U.K.
⁸Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K.
⁹School of Social and Community Medicine, University of Bristol, Bristol, U.K.
¹⁰Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
¹¹Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
¹²Metabolic Unit, Western General Hospital, Edinburgh, U.K.
¹³Genetics Division, Research and Development, GlaxoSmithKline, Harlow, U.K.
¹⁴Centre for Clinical Pharmacology, University College London, London, U.K.

Corresponding author: Philippa J. Talmud, p.talmud{at}ucl.ac.uk.

Diabetes 2015 May; 64(5): 1830-1840. https://doi.org/10.2337/db14-1504

Article Figures & Tables

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Figure 1
Forest plot showing the 10% detection rate for all seven studies for (A) the Framingham phenotypic score alone and (B) Framingham T2D score plus the externally weighted gene score. DR10, 10% detection rate.
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Figure 2
The distribution of the 65-SNP gene score, weighted by the external published β-values in the combined studies. Superimposed are the log ORs for T2D.
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Figure 3
The receiver operating curve for the seven combined studies.
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Figure 4
Scatter plot showing the correlation between Framingham T2D score and Framingham T2D score plus the externally weighted gene score. A: Those who remained T2D free. B: Incident T2D cases.

Tables

Figures

Table 1

Total number of individuals, T2D rates, and baseline characteristics of subjects for incident T2D in the seven studies

	BRHS	BWHHS	EAS	MRC NSHD	WHII	ELSA	CAPS	Total
Number included in analysis	2,317	1,854	703	2,410	3,045	1,685	1,280	13,294
Number with incident T2D (%)	150 (6.5)	103 (5.6)	16 (2.3)	118 (4.9)	219 (7.2)	74 (4.4)	124 (9.7)	804 (6.1)
Length of follow-up, years	20	7	12	10	10	4	15.5	11.2
Rate per 1,000 person-years	3.2	7.9	1.9	4.9	7.2	11.0	6.3	5.4
Age, years	49.1 (5.6)	70.8 (5.3)	64.5 (5.6)	53.0 (0)	48.9 (6.0)	73.6 (9.1)	56.7 (4.5)	57.4 (11.2)
Sex, % male (n)	100% (2,317)	0% (0)	46.8% (329)	49.9% (1,203)	76.7% (2,336)	51.8% (873)	100% (1,280)	62.7% (8,338)
BMI, kg/m²	25.4 (2.9)	27.5 (4.8)	25.3 (3.6)	27.3 (4.6)	25.2 (3.5)	27.2 (4.2)	26.6 (3.6)	26.3 (4.1)
HDL, mmol/L	1.15 (0.24)	1.63 (0.44)	1.47 (0.37)	1.68 (0.49)	1.42 (0.40)	1.51 (0.38)	1.03 (0.25)	1.42 (0.44)
Triglyceride, mmol/L^*	1.87 (0.81)	1.71 (0.76)	1.35 (0.58)	1.82 (1.01)	1.22 (0.67)	1.56 (0.77)	1.70 (0.85)	1.58 (0.83)
Systolic blood pressure, mmHg	144.6 (20.5)	154.3 (27.2)	142.7 (23.4)	138.0 (21.2)	121.1 (13.9)	146.1 (20.4)	145.9 (22.5)	139.6 (23.6)
Diastolic blood pressure, mmHg	82.2 (13.3)	83.1 (13.0)	77.1 (12.1)	85.8 (13.0)	80.1 (9.7)	77.9 (11.5)	84.5 (11.7)	81.9 (12.3)
Fasting glucose, mmol/L^*	5.43 (0.92)	5.79 (0.70)	5.49 (0.56)	5.94^† (0.78)	5.19 (0.45)	5.38 (0.77)	5.20 (0.67)	5.48 (0.76)

Data are presented as mean (SD) unless otherwise indicated. Patients with type 1 diabetes or latent autoimmune diabetes of adulthood were excluded.
*Geometric mean (approximate SD).
†Calculated from nonfasting HbA_1c.

Table 2

Quintiles of FORS and externally weighted 65-gene score in the combined studies

Quintile	FORS	Externally weighted gene score	FORS and externally weighted gene score
1	1.00	1.00	1.00
2	2.83 (1.93–4.15)	1.37 (1.05–1.79)	2.62 (1.76–3.92)
3	4.28 (2.97–6.17)	1.36 (1.04–1.78)	4.73 (3.23–6.92)
4	7.76 (5.39–11.16)	2.01 (1.56–2.58)	7.74 (5.32–11.27)
5	21.07 (14.86–29.88)	2.70 (2.12–3.43)	22.59 (15.75–32.41)
Per quintile	2.07 (1.94–2.21); P = 2.60 × 10⁻¹⁰⁶	1.28 (1.21–1.34); P = 9.03 × 10⁻²⁰	2.12 (1.99–2.27); P = 7.71 × 10⁻¹¹¹
Per SD	2.70 (2.48–2.93); P = 5.40 × 10⁻¹²¹	1.43 (1.33–1.54); P = 2.25 × 10⁻²²	2.83 (2.61–3.08); P = 3.08 × 10⁻¹³²

Data are presented as OR (95% CI).

Table 3

A_ROC (95% CI) and the false-positive detection rates for the combined data

	OR (95% CI) top vs. bottom quintile	A_ROC for combined studies (95% CI)	Detection rate for 5% false positive (95% CI)	Detection rate for 10% false positive (95% CI)
Externally weighted gene score	2.70 (2.12–3.43)	0.60 (0.58–0.62)	11.75% (9.54–13.95)	19.89% (17.14–22.63)
FORS	21.07 (14.86–29.88)	0.75 (0.73–0.77)	18.56% (15.9–21.22)	30.67% (27.51–33.82)
FORS + externally weighted gene score	22.59 (15.75–32.41)	0.76 (0.75–0.78)^*	23.14% (20.23–26.05)	37.28% (33.95–40.61)

*P = 0.003. P value derived from the comparison with FORS alone.

Table 4

NRI based on addition of gene score to FORS, calculated using risk cutoffs of 5, 10, and 15% for 10-year risk

Predicted risk FORS	Number of people				Reclassified		Net correctly reclassified
Predicted risk FORS	≤5	5–9.9	10–14.9	≥15	Increased risk	Decreased risk	Net correctly reclassified
A. For the whole cohort
Plus externally weighted gene score: no diabetes (n = 18,715.81)					1,782.23	2,138.63	1.9% (1.2–32.6)
<5	10,406.62	582.00	36.28	0
5–9.9	1,064.52	1,967.29	542.56	118.24
10–14.9	35.16	647.23	682.39	503.15
≥15	6.55	78.89	306.28	1,738.65
Plus externally weighted gene score: incident diabetes (n = 1,121.86)					185.96	116.49	6.2% (3.2–9.2)
<5	279.01	34.13	1	0
5–9.9	36.80	81.20	55.97	15.82
10–14.9	0	45.93	71.24	79.04
≥15	0	11.73	22.03	387.96
B. BMI tertile 1 (BMI <24.5)
Plus externally weighted gene score: no diabetes (n = 6,267.82)					448.8	616.52	2.7% (1.7–3.7)
<5	4,202.14	95.95	2	0
5–9.9	540.06	834.1	232.65	63.3
10–14.9	1	35.27	36.08	54.9
≥15	0	7.13	33.06	130.18
Plus externally weighted gene score: incident diabetes (n = 147.53)					45.88	9.13	24.9% (15.0–34.8)
<5	56	3	0	0
5–9.9	6.13	21.06	26.32	7.82
10–14.9	0	3	2.21	8.74
≥15	0	0	0	13.25
C. BMI tertile 2 (BMI 24.5–27.4)
Plus externally weighted gene score: no diabetes (n = 6,526.66)					706.02	715.15	0.1% (−1.0 to 1.3)
<5	3,684.61	267.53	22.95	0
5–9.9	339.91	675.31	185.82	34.24
10–14.9	20.83	253.93	266.22	195.48
≥15	6.55	22.56	71.37	479.35
Plus externally weighted gene score: incident diabetes (n = 308.31)					58.26	22.93	11.5% (5.7–17.2)
<5	112.17	17.13	0	0
5–9.9	7.13	23.63	12.25	6
10–14.9	0	11.66	18.64	22.88
≥15	0	1	3.14	72.68
D. BMI tertile 3 (BMI ≥27.5)
Plus externally weighted gene score: no diabetes (n = 5,921.35)					627.42	806.96	3.0% (1.8–4.3)
<5	2,519.87	218.52	11.33	0
5–9.9	184.55	457.88	124.09	20.71
10–14.9	13.33	358.03	380.1	252.77
≥15	0	49.2	201.85	1,129.12
Plus externally weighted gene score: incident diabetes (n = 666.02)					81.82	84.43	−0.4% (−4.2 to 3.4)
<5	110.83	14	1	0
5–9.9	23.55	36.52	17.4	2
10–14.9	0	31.26	50.39	47.42
≥15	0	10.73	18.89	302.03

A. Values are weighted to take into account sampling design, thus accounting for the fact that the number of individuals is not an integer. P value for heterogeneity = 0.002. I² = 71.1%. NRI (95% CI) = 8.1% (5.0–11.2), no adjustment for study; P = 3.31 × 10⁻⁷. NRI (95% CI) = 6.6% (3.6–9.7), results from meta-analysis of individual study results (fixed effects); P = 2.0 × 10⁻⁵. NRI (95% CI) = 7.7% (1.7–13.8), results from meta-analysis of individual study results (random effects); P = 0.01. B. NRI (95% CI) = 27.6% (17.7–37.5); P = 4.82 × 10^–8. C. NRI (95% CI) = 11.6% (5.8–17.4); P = 9.88 × 10^–5. D. Values are weighted to take into account sampling design, thus accounting for the fact that the number of individuals is not an integer. NRI (95% CI) = 2.6% (−1.4 to 6.6); P = 0.20.