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Journal of Peking University (Health Sciences) ›› 2021, Vol. 53 ›› Issue (3): 453-459. doi: 10.19723/j.issn.1671-167X.2021.03.003

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Genetic study of cardiovascular disease subtypes defined by International Classification of Diseases

GUO Zi-ning,LIANG Zhi-sheng,ZHOU Yi,ZHANG Na,HUANG JieΔ()   

  1. Department of Global Health, School of Public Health, Peking University 100191, China
  • Received:2021-01-22 Online:2021-06-18 Published:2021-06-16
  • Contact: Jie HUANG E-mail:jiehuang001@pku.edu.cn
  • Supported by:
    National Key Research and Development Program of China(2020YFC2002900);Peking Univerity Research Initiation Fund(BMU2018YJ009)

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Abstract:

Objective: To study the molecular connection among cardiovascular diseases (CVD) subtypes defined by the International Classification of Diseases (ICD) version 10 (ICD-10). Methods: Both phenotypic data and genotypic data used in this study were obtained from the UK Biobank. A total of 380 083 participants aged between 40 and 69 years were included. Those without any cardiovascular disease (either no ICD-10 code at all or no ICD-10 code containing letter I) were assigned to the control group. The five CVD subtypes were: ischaemic heart diseases (IHD), pulmonary heart disease and diseases of pulmonary circulation (PHD), cerebrovascular diseases (CRB), diseases of arteries, arterioles and capillaries (AAC), diseases of veins, lymphatic vessels and lymph nodes, and diseases not elsewhere classified (VLL). We first performed a genome-wide association study (GWAS) for each of the five subtypes. We summarized novel loci using genome-wide significance threshold P=5×10-8. Next, we used linkage disequilibrium score regression (LDSC) method to assess genetic correlation among the five subtypes. Lastly, we applied mendelian randomization (MR) approach to assess the causal relationship among the subtypes. The particular software that we used was generalised summary-data-based mendelian randomisation (GSMR). Results: Through GWAS, we identified hundreds of genome-wide significant SNPs: 672 for IHD, 241 for PHD, 31 for CRB, 48 for AAC, and 193 for VLL. By comparing with published literature, we found 28 novel loci, for PHD (n=14), CRB (n =7) and AAC (n =7). Eight of these 28 loci were rare, where the lead SNP had minor allele frequency (MAF) less than 1%. LDSC analyses indicated IHD had significant genetic correlation with VLL (P=2.52×10-7), PHD (P=3.77×10-3) and AAC (P=4.90×10-3), respectively. Bidrectional GSMR analyses showed that IHD had a positive causal relationship with VLL (P=7.40×10-5) and AAC (P=1.50×10-3), while reverse causality was not supported. Conclusion: This study adopted an innovative approach to study the molecular connection among CVD subtypes that are defined by ICD. We identified potentially positive genetic correlation and causal effects among some of these subtypes. Research along this line will provide scientific insights and serve as a guidance for future ICD standards.

Key words: International classification of diseases, Cardiovascular diseases, Genome-wide association studies, Genetic correlation, Mendelian randomization

CLC Number: 

  • R54

Table 1

Characteristics of participants in five cardiovascular diseases (CVD) subtypes and in control group"

Items IHD PHD CRB AAC VLL Control group
n 13 554 1 631 3 680 2 609 28 220 246 437
Age/years 60.51±6.44 59.07±7.21 59.60±7.21 59.27±7.29 57.07±7.77 55.10±8.01
Male, n(%) 8 800 (64.93) 807 (49.48) 1 987 (53.99) 1 303 (49.94) 11 813 (41.86) 105 177 (42.67)
BMI/(kg/m2) 28.80±4.73 28.79±5.18 27.77±4.68 27.12±4.83 27.58±4.83 26.70±4.41
Height/cm 169.53±9.03 169.74±9.61 168.39±9.23 168.16±8.99 168.53±9.23 168.70±9.19
Current smoker(including ex-smoker), n(%) 7 671
(56.60)		 782
(47.95)		 2 005
(54.48)		 1 678
(64.32)		 13 218
(46.84)		 104 892
(42.56)
Current drinker(including ex-drinker), n(%) 13 021
(96.07)		 1 576
(96.63)*		 3 536
(96.09)		 2 512
(96.28)*		 27 242
(96.53)		 239 343
(97.12)

Figure 1

Manhattan plots of five CVD subtypes IHD, ischaemic heart diseases; PHD, pulmonary heart disease and diseases of pulmonary circulation; CRB, cerebrovascular diseases; AAC, diseases of arteries, arterioles and capillaries; VLL, diseases of veins, lymphatic vessels and lymph nodes, not elsewhere classified."

Table 2

Significant loci associated with CVD subtypes"

Items Significant SNPs Significant loci Novel loci Rare loci
IHD 672 17 0 0
PHD 241 32 14 5
CRB 31 11 7 2
AAC 48 17 7 1
VLL 193 6 0 0

Table 3

Novel loci associated with five cardiovascular diseases (CVD) subtypes"

Disease Chromosome Position Single nucleotide polymorphisms P A1 A2 Minor allele frequency
PHD 4 12883807 rs73215670 1.96×10-10 A G 1.10×10-3
5 118562026 rs184455971 2.58×10-8 A G 1.40×10-3
6 103119329 rs114664439 3.85×10-8 C A <1×10-5
7 38266212 rs138663704 9.90×10-11 A T 2.80×10-3
8 69402863 rs534733210 2.23×10-8 T A 2.10×10-3
8 142854164 rs12545168 2.19×10-8 A T <1×10-5
11 121066124 rs17124940 1.61×10-9 C A 1.00×10-4
11 129600984 rs115956442 3.82×10-9 T G 1.00×10-4
13 25166811 rs142279518 3.59×10-9 T G 2.00×10-4
13 77044683 rs73545476 3.22×10-8 G A 2.00×10-4
14 83677831 rs371991088 3.36×10-8 C G 1.00×10-4
14 96624944 rs566847514 3.59×10-8 T G 1.50×10-3
15 45200618 rs9989321 5.93×10-9 A C 3.00×10-4
15 98637990 rs138967775 7.21×10-9 G A 1.00×10-4
CRB 2 222233437 rs572911615 2.71×10-8 A G 1.90×10-3
8 69390845 rs113300185 7.59×10-9 T A 1.10×10-3
17 72008650 rs73998648 4.73×10-8 G A 1.00×10-4
X 41277264 rs113507059 4.85×10-8 G T 2.00×10-4
X 63179140 X:63179140 2.79×10-8 A C 4.00×10-4
X 66983983 rs5919421 1.48×10-8 A G 4.00×10-4
X 103223335 rs57674601 1.77×10-8 A T 2.00×10-4
AAC 1 245201511 rs649445 6.50×10-10 A G 6.00×10-4
10 98204792 rs558155932 2.50×10-8 G A 2.00×10-4
11 38306906 rs551810096 1.78×10-9 C T 3.00×10-4
14 19431761 rs368924711 9.44×10-9 A G 7.00×10-4
15 54487816 rs140569087 1.46×10-8 C T 4.00×10-4
17 13367363 rs114817801 6.82×10-9 G A 1.00×10-4
20 12020603 rs185329711 1.15×10-8 T C 1.30×10-3

Figure 2

LocusZoom plot of the chromosome X locus associated with CRB LD ref var, linkage disequilibrium reference variant."

Table 4

Genetic correlations among five CVD subtypes"

Subtype 1 Subtype 2 Rg SE Z P h2 h2se
IHD VLL 0.30 0.059 5.2 2.52×10-7* 0.02 2.00×10-3
IHD PHD 0.40 0.137 2.9 3.77×10-3* 6.00×10-3 2.00×10-3
IHD AAC 0.74 0.263 2.8 4.90×10-3* 0.03 3.00×10-3
AAC CRB 1.93 1.609 1.2 0.23 1.00×10-3 2.00×10-3
IHD CRB 0.84 0.624 1.4 0.18 0.03 3.00×10-3
CRB PHD 0.47 0.669 0.7 0.49 5.00×10-3 2.00×10-3
AAC VLL 0.34 0.199 1.7 0.09 0.02 2.00×10-3
PHD VLL 0.14 0.120 1.2 0.24 0.02 2.00×10-3
CRB VLL 0.08 0.260 0.3 0.75 0.02 2.00×10-3
AAC PHD 0.00 0.328 0.0 0.99 5.00×10-3 2.00×10-3

Table 5

Mendelian randomization based causal effects among CVD subtypes"

Subtype 1 Subtype 2 Beta SE P N Reverse-beta Reverse-SE Reverse-P Reverse-N
IHD VLL 0.10 0.03 7.40×10-5* 28 0.14 0.06 0.01 26
IHD CRB 0.19 0.05 1.80×10-4* 1 0.00 0.04 0.92 20
PHD AAC 0.12 0.04 1.50×10-3* 5 0.22 0.08 0.01 35
IHD AAC 0.18 0.06 1.80×10-3* 4 0.01 0.03 0.65 35
PHD VLL 0.03 0.01 4.10×10-3 5 0.14 0.16 0.39 26
IHD PHD 0.12 0.07 0.08 4 0.02 0.02 0.33 35
PHD CRB 0.05 0.03 0.09 5 0.11 0.11 0.32 20
AAC VLL 0.04 0.02 0.10 5 0.03 0.13 0.81 25
CRB AAC 0.13 0.08 0.14 0 0.04 0.06 0.46 35
CRB VLL 0.02 0.03 0.47 0 0.05 0.10 0.65 26
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