Familial Aggregation and Heritability of Congenital Heart Defects

Abstract

Background: Congenital heart defects (CHD) are known to cluster within families, but existing evidence varies for the estimates of familial relative risk (RR). We aimed to examine familial aggregation and heritability of CHD in the general population of Taiwan.

Methods and Results: We conducted a population-based family study using the Taiwan National Health Insurance (NHI) research database. Individuals with affected first-degree (n=295,636) or second-degree (n=73,985) relatives were identified from all NHI beneficiaries (n=23,422,955) registered in 2012. Diagnoses of CHD for all study subjects were ascertained between January 1, 1996 and December 31, 2012. Having a twin, a first-degree relative and an affected second-degree relative were associated with an adjusted RR of 12.03 (11.59–12.49), 4.91 (4.85–4.97) and 1.21 (1.14–1.28) for CHD, respectively. Individuals with 1 affected first-degree relative had a RR of 4.78 (4.72–4.84), and those with ≥2 had an RR of 7.10 (6.77–7.45) for CHD. The estimated accountability for phenotypic variance of CHD was 37.3% for familial transmission and 62.8% for non-shared environmental factors.

Conclusions: Our results indicated that CHD tend to cluster within families, and approximately one-third of phenotypic variance was explained by familial factors.

Congenital heart defects (CHD) are the most common congenital disorder.¹ The prevalence of CHD in the adult population has increased gradually in the past several decades because of advances in modalities to detect subtle anatomical abnormalities.^2,3 Using data from the Taiwan National Health Insurance (NHI) database, the CHD prevalence has been estimated at 13.08 per 1,000 live births, with ventricular septal defect (VSD) at 4.0 per 1,000 live births, secundum atrial septal defect (ASD) at 3.2 per 1,000 live births, patent ductus arteriosus (PDA) at 2.0 per 1,000 live births, pulmonary stenosis at 1.2 per 1,000 live births, and tetralogy of Fallot (TOF) at 0.63 per 1,000 live births.⁴

Clinical observations generally suggest a greater risk of CHD in family members of affected patients, which suggests the importance of heredity in CHD. Previous studies have identified over 50 gene mutations associated with specific types of CHD.^5,6 However, population estimates of familial risks are less frequently reported. A British collaborative study identified 727 individuals with major cardiac defects requiring surgical correction and 393 live offspring, and reported a recurrence risk of 4.1% in offspring and 2.1% in siblings.⁷ The 2 population-based studies based on data from Danish registers found an up to 80-fold increased risk of specific types of CHD in first-degree relatives,⁸ and strong familial aggregation of discordant CHD phenotypes.⁹ However, no excess clustering of specific CHD phenotypes was found among the first-degree relatives. These findings suggest both genetic and shared environmental factors contribute to the susceptibility to CHD. However, only specific types of CHD, such as bicuspid aortic valve or left ventricular outflow tract obstruction, have been assessed for heritability, which is estimated at 70%.^10,11

Therefore, we conducted a nationwide study comprising essentially the entire population of Taiwan in 2012. Using nationwide genealogy and linked health information derived from the NHI database, we determined familial clustering of CHD by estimating the risks of CHD according to specific affected kinship and assessed the relative contribution of genetic and environmental factors to CHD susceptibility.

Methods

Study Population

This study was approved by the Institutional Review Board of the Chang Gung Memorial Hospital and the Ministry of Health and Welfare (the data holder of the NHI research database). We constructed a cohort comprising NHI beneficiaries actively registered in 2012 using data from the Registry for NHI Beneficiaries, Registry for Catastrophic Illness Patients and datasets of ambulatory care expenditures and details of ambulatory case orders, all of which are constituents of the NHI database. The major research steps involved constructing a nationwide cohort, identifying patients with CHD, reconstructing a nationwide genealogy reconstruction, estimating familial risks and calculating familial transmission.

The Taiwan NHI program initiated its nationwide coverage in 1995 with a single-payer insurance system. All citizens in Taiwan are required to enrol in the program by law and subsidies are granted for those cannot pay for premium, thereby resulting in an exceptionally high coverage rate of 99.5% in 2010.¹² Currently, there are 27,476 contracted medical facilities providing primary to specialist care. The NHI database has recorded comprehensive personal information including sex, date of birth, place of residence, details of insurance, family relationships, vital status and details of clinical information including dates of inpatient and outpatient visits, medical diagnoses, medical expenditures, prescription details, vaccination status, examinations, operations and procedures. Personal identification is encrypted before releasing the data to researchers, thus remaining unique for each beneficiary in the database to facilitate internal records linkage.

Methods for genealogy reconstruction using recorded family relationships in the NHI database have been previously reported.^13–15 The Registry of Beneficiaries is the primary data source for family relationships between blood descendants or ascendants up to 2 generations or spouse. This allows us to identify parents, offspring, full siblings, twins and spouse of NHI beneficiaries. We also developed an algorithm to indirectly identify parent–offspring relationships.^13–15 Full siblings were individuals with the same parents. Twins were full siblings with the same date of birth (±1 day), but twin zygosity cannot be derived from the database. We identified possible family links by incorporating the entire registry records from 1995 to 2012.

Next, we used the family relationships to assemble pedigrees. Among 29,505,197 individuals contained in the registry of beneficiaries, we identified 4,042,209 families with a mean family size of 5.4 persons and 2–5 generations in these families. (Note that each individual may appear multiple times in different categories of family relationships depending on family structure.)

Ascertainment of CHD

In Taiwan, patients with suspected CHD are referred to cardiologists for diagnosis and treatment. In general, cardiologists in the medical centers care for the majority of patients with CHD. Patients with diagnosed CHD are entitled to a waiver of medical co-payment. Diagnostic information is forwarded to the insurance administration for review by commissioned expert panels to confirm the diagnosis before waivers are approved. The Registry for Catastrophic Illness Patients contains information about these patients protected by unique personal identification, including diagnosis, demographics, application date, diagnosing physician and hospital and other administration data. We used this registry to identify patients with CHD (International Classification of Diseases, 9th version [ICD-9] codes 745–747, excluding 746.86, 747.5–747.9). Some patients with a milder form of CHD may not be given catastrophic illness certification. To enhance the identification of CHD patients, we also identified patients with the aforementioned ICD-9 codes by cardiologists in hospitalization records or outpatient records in medical centers. This type of case definition has been applied in previous studies.³

Statistical Analysis

The prevalence of CHD was calculated for the general population and for individuals with affected first-degree family members. We calculated adjusted prevalence ratios of CHD (relative risk (RR)) between first-degree relatives of an individual with CHD and the general population, which is essentially the relative recurrence risk according to the original Risch definition.¹⁶ Cox proportional hazards models were used to estimate adjusted prevalence ratios by applying an equal follow-up time for all subjects, which has been validated previously with valid estimates.^17–19 Family members naturally cluster with each other; this within-family clustering was handled by the marginal model,²⁰ which has found to produce comparable RR and 95% confidence intervals (CIs) with the frailty model.²⁰ The RR was adjusted for age, sex, socioeconomic factors and family size. Details of socioeconomic factors have been reported in our previous studies.^13–15 This approach has been applied before and validated previously for other diseases.²¹

We calculated the RRs for individuals with an affected first-degree relative of any kinship and for individual first-degree (parent, sibling and twin) and second-degree kinship (aunt, uncle, nephew and niece). In addition, we fitted models separately according to kinship and the sex of affected relatives (parent, sibling, twin aunt, uncle, nephew and niece). Twins were excluded from the sibling analyses. The RR was estimated for individuals with 1 or 2 affected first-degree relatives with the risk in the general population.

Heritability was genetic contribution to total phenotypic variance and familial transmission was genetic plus shared environmental contributions, both of which were calculated using the polygenic liability model to calculate both measures.^22–24 In this study, we were unable to differentiate the shared environmental and genetic contributions to phenotypic variance, despite the fact that only twins share the in utero environment. We consider that shared environmental contribution should be minimal in the case of CHD; however, we still reported familial transmission rather than heritability. Statistical hypothesis was performed on the 2-sided 5% level of significance. All analyses were performed using SAS v. 9.3 (SAS Institute, Cary, NC, USA).

Results

CHD Prevalence in Individuals With Affected First-Degree Family Members vs. the General Population

The study population comprised 23,245,523 individuals enrolled in the NHI database in Taiwan in 2012. Among them, 46.70%, 56.79%, 46.69% and 1.47% had a known parent, child, sibling or twin, respectively. We identified 216,938 patients who were diagnosed with CHD, generating a crude prevalence of 0.93% (Table 1) and the most common CHD subtypes were ASD, VSD, PDA and TOF.

Table 1. Baseline Characteristics of Individuals With Affected First- and Second-Degree Relatives With CHD and the General Population

	With affected first-degree relative	With affected second-degree relative	General population
n	295,636	73,985	23,422,955
Male, n (%)	146,175 (49.44)	39,474 (53.35)	11,439,444 (49.21)
Age (years) (mean±standard deviation)	17.6±12.0	35.8±12.2	38.6±20.9
CHD, n (%)	26,425 (8.94)	765 (1.03)	216,938 (0.93)

CHD, congenital heart defects.

In the general population of Taiwan in 2012, 295,636 (1.27%) individuals had at least 1 first-degree relative with CHD: 76,949 with affected parents, 221,134 with affected sibling and 8,206 with affected twins. The age-specific prevalence of CHD was higher in individuals with affected first- or second-degree relatives with CHD than in the general population (Figure).

Figure.

Age-specific prevalence of congenital heart defects (CHD) in individuals with an affected first- or second-degree relative (solid circles) and in the general population (empty circle) in Taiwan in 2012. Age-specific prevalence curves show that individuals with an affected first-degree relative have a higher prevalence than the general population until 65 years of age.

RR for CHD in Individuals With Affected First-Degree Relatives

Prevalence (recurrence risk) of CHD in individuals with affected first- and second-degree relatives of specific types is shown in Table 2 and Table 3, respectively.

Table 2. (A) RRs for CHD in Twin First-Degree Relatives, (B) RR for CHD in Twin Second-Degree Relatives

Type of affected relative / Sex of affected relative	Sex of individual	No. of cases	Prevalence (%)	RR (95% CI)*
A
Twin
Male	Male	1,012	35.16	12.21 (11.47–12.99)
	Female	407	34.23	11.47 (10.6–12.4)
	All	1,419	34.89	12.26 (11.66–12.9)
Female	Male	410	32.46	10.95 (10.11–11.85)
	Female	1,045	35.60	12.74 (12–13.53)
	All	1,455	34.66	11.89 (11.33–12.49)
All	Male	1,405	34.17	11.76 (11.18–12.37)
	Female	1,437	35.10	12.33 (11.74–12.94)
	All	2,842	34.63	12.03 (11.59–12.49)
B
Any
Male	Male	4,957	7.96	3.65 (3.52–3.77)
	Female	4,812	7.25	5.07 (4.97–5.16)
	All	9,769	7.59	4.46 (4.39–4.54)
Female	Male	8,754	9.96	4.62 (4.53–4.7)
	Female	9,461	10.78	6.05 (5.93–6.17)
	All	18,215	10.37	5.42 (5.34–5.49)
All	Male	12,975	8.88	4.11 (4.04–4.18)
	Female	13,450	9.00	5.52 (5.45–5.6)
	All	26,425	8.94	4.91 (4.85–4.97)
Parent
Male	Male	385	3.21	2.7 (2.44–2.98)
	Female	377	3.57	2.43 (2.19–2.69)
	All	762	3.38	2.55 (2.37–2.74)
Female	Male	4,771	17.00	7.57 (7.39–7.75)
	Female	4,815	18.11	7.36 (7.19–7.54)
	All	9,586	17.54	7.45 (7.32–7.57)
All	Male	5,108	12.80	6.62 (6.47–6.77)
	Female	5,147	13.90	6.36 (6.22–6.51)
	All	10,255	13.33	6.47 (6.37–6.58)
Sibling
Male	Male	3,644	7.68	3.33 (3.19–3.47)
	Female	4,023	7.38	3.24 (3.14–3.33)
	All	7,667	7.52	3.27 (3.18–3.35)
Female	Male	3,955	6.49	3.27 (3.18–3.37)
	Female	4,067	6.71	3.28 (3.15–3.41)
	All	8,022	6.60	3.28 (3.2–3.36)
All	Male	7,389	6.88	3.24 (3.16–3.33)
	Female	7,817	6.87	3.19 (3.11–3.27)
	All	15,206	6.88	3.21 (3.14–3.28)

*Adjusted for age, sex, place of residence, quintiles of income level, occupation and family size. CHD, congenital heart defects; CI, confidence interval; RR, relative risk.

Table 3. RRs for CHD in Second-Degree Relatives

Type of affected relative / Sex of affected relative	Sex of individual	No. of cases	Prevalence (%)	RR (95% CI)*
Any
Male	Male	104	0.53	1.19 (1.04–1.36)
	Female	197	1.15	1.19 (1.09–1.3)
	All	301	0.82	1.19 (1.1–1.28)
Female	Male	193	0.93	1.19 (1.08–1.3)
	Female	291	1.60	1.29 (1.16–1.43)
	All	484	1.24	1.24 (1.15–1.34)
All	Male	292	0.74	1.18 (1.09–1.28)
	Female	473	1.37	1.24 (1.15–1.33)
	All	765	1.03	1.21 (1.14–1.28)
Aunt/uncle
Male	Male	54	2.79	1.42 (1.08–1.86)
	Female	53	2.83	1.31 (1–1.73)
	All	107	2.81	1.36 (1.11–1.66)
Female	Male	141	3.62	1.43 (1.22–1.68)
	Female	144	4.03	1.44 (1.22–1.69)
	All	285	3.82	1.43 (1.27–1.61)
All	Male	194	3.34	1.42 (1.24–1.64)
	Female	195	3.59	1.39 (1.21–1.6)
	All	389	3.46	1.4 (1.27–1.55)
Niece/nephew
Male	Male	50	0.28	1.12 (0.85–1.48)
	Female	143	0.94	1.37 (1.16–1.61)
	All	193	0.59	1.3 (1.13–1.49)
Female	Male	51	0.30	1.22 (0.93–1.61)
	Female	147	1.00	1.48 (1.26–1.74)
	All	198	0.63	1.41 (1.23–1.63)
All	Male	98	0.29	1.16 (0.95–1.41)
	Female	278	0.96	1.4 (1.24–1.57)
	All	376	0.60	1.33 (1.2–1.47)

*Adjusted for age, sex, place of residence, quintiles of income levels, occupation and family size. Abbreviations as in Table 2.

The RRs (95% CIs) for CHD were associated with the degree of genetic distance between family relatives. Overall, having an affected co-twin (50% or 100% genetic similarity depending on zygosity), first-degree relative (on average 50% genetic similarity), or second-degree relative (on average 25% genetic similarity) was associated with an adjusted RR of 12.03 (11.59–12.49), 4.91 (4.85–4.97), and 1.21 (1.14–1.28), respectively. The adjusted RRs for the CHD subtypes in siblings were associated with 5.2 (4.94–5.48) for ASD, 3.60 (3.16–4.11) for VSD, 4.76 (4.22–5.38) for PDA and 22.08 (13.87–35.16) for TOF, respectively (Table S1).

In addition, the RRs increased with the number of affected first-degree relatives. Compared with the general population, individuals with 1 affected first-degree relative had an RR (95% CI) of 4.78 (4.72–4.84), and those with ≥2 had an RR of 7.10 (6.77–7.45) for CHD. The sex of an affected relative seemed to affect the RR for CHD. For example, the RR (95% CI) for individuals with affected male relatives was 4.46 (4.39–4.54), but it was 5.42 (5.34–5.49) for those with affected female relatives. RR for CHD was found in individuals with affected second-degree relatives of different sexes (Table 3). RRs (95% CI) were 3.21 (3.14–3.28) for those with affected siblings, 6.47 (6.37–6.58) for those with affected parents, 1.40 (1.27–1.55) for those with affected aunts or uncles, and 1.33 (1.20–1.47) for those with affected nieces or nephews.

Familial Resemblance and Heritability of CHD

Using a threshold liability model, we estimated that the accountability for phenotypic variance of CHD was 37.3% for familial transmission, and 62.8% for non-shared environmental factors. Given those parameters that have been previously estimated, the probability of a patient having CHD that is likely to be sporadic was 82.6%.

Discussion

This population-based study compared the prevalence of CHD between individuals with a family history and the general population using data derived from the entire 2012 general Taiwanese population. We found that a positive family history of CHD was associated with a 5-fold increased risk of CHD. Additionally, the risk of CHD was associated with the genetic distance, which suggests the importance of genetic factors in the susceptibility to CHD. Using threshold liability mode, we determined that approximately one-third of CHD phenotypic variance was accounted for by familial factors. Despite a high family risk, it seems that the majority of patients were expected to have sporadic disease. Overall, family history was a strong risk factor for CHD and our data suggested that both genetic and environmental factors accounted for the overall liability of CHD. Therefore, our data should be valuable for genetic counselling of CHD patients.

Our study indicated that a positive family history was a strong risk factor for CHD, with a 5-fold RR in first-degree relatives of CHD patients. Despite this, expected familial transmission was approximately 40%, suggesting that non-familial factors also accounted for a large proportion of phenotypic variance. Our results were consistent with previous studies. Shieh et al reported that consanguineous unions resulted in a greater risk for CHD.²⁵ Oyen et al reported that a family history is associated with 3-fold greater risk of CHD;⁸ however, only 2.2–4.2% of the CHD population can be attributed to CHD family history.^8,26 Another study reported by Zaidi et al reported that de novo mutation, which is not transmitted in families, was found in 10% of patients with sporadic severe CHD, who may or may not have had a family history.²⁷ In those cases, direct sequencing may identify novel genetic contributions to CHD.^27,28 In this regard, a large-scale genome-wide association study may have a limited role in the elucidation of candidate genes controlling the occurrence of CHD, because (1) the estimated heritability of CHD is moderate (theoretically cannot exceed familial transmission, which is the sum of heritability and shared environmental contribution), (2) the prevalence of CHD is low, and (3) de novo mutations are rare variants that may not be enriched in the study population.

We found a higher risk of CHD in maternal affected cases than in paternal affected cases. Regarding the maternal issue, there are few reports and conflicting evidence, primarily from Western countries, including America and Europe.^7,29 Because CHD is congenital, it is unlikely that shared familial environment, other than the in utero environment, has a profound effect on the risk. For example, maternal exposure to smoking, toxins, and drugs has been suggested to increase the risks of CHD.^30–32 Recently, more evidence has shown that some maternal chronic diseases, such as diabetes mellitus, connective tissue disease, hypertension, thyroid disorders and epilepsy, are associated with sibling’s CHD.^33,34 Some associated mechanisms have been postulated, such as drug and tobacco exposure, poor glycemic control in the first trimester of pregnancy and inflammation interaction effect, for the disruption of fetal heart development. Some of these maternal factors are modifiable, therefore more studies should be undertaken to confirm these associations between maternal chronic illness and maternal use of/exposure to these agents and the risk of CHD, which may facilitate prenatal counselling.

The advent of ultrasound technology has led to the possibility of prenatal screening for severe CHD, and a greater chance to identify occult CHD early in infancy. Progress in echocardiographic capabilities, together with improved clinical management, has resulted in a substantial increase in the prenatal diagnosis of CHD.^35–37 Progress in these areas may influence our estimates for familial risk. First, prenatal identification of severe CHD may lead to pregnancy termination, particularly in recent years when level 2 prenatal ultrasound became a routine part of prenatal care in Taiwan. Second, beyond echocardiography, some parents may do genetic screening, either self-paid or insurance covered, such as for Down syndrome, and that may also lead to early pregnancy termination. All of these may lead to an underestimation of sibling RRs, which was also shown in our data when comparing offspring and parental risks. Third, the chance of occult CHD identification is higher in the younger generation, which may lead to a slight overestimation of CHD prevalence in offspring. However, our case definition was based on catastrophic illness certification, which cardiologists tend not to give to patients with nonfatal occult CHD. Therefore, the effect may be minimal. However, the true effect of ultrasound for CHD screening in the estimation of familial risks needs further study to confirm.

Study Limitations

First, the case definitions were based purely on the diagnosis recorded by physicians. We did not have detailed information on patients’ clinical findings, including environmental exposure such as smoking, and could not validate the diagnosis. Nevertheless, granting catastrophic illness certification requires strong clinical evidence for a diagnosis of CHD, which is agreed by an expert panel. Cardiologists’ diagnoses of CHD for patients with a lesser severity CHD is generally based on echocardiographic evidence. Therefore, our case definitions were stringent. Second, zygosity of twins is not recorded in the database. Third, because we estimated familial transmission using the threshold liability model, which assumes liability underlying a disease is normally distributed in the population. Fourth, this study was restricted to Taiwan, and different findings may occur in different populations and in different environments. Therefore, further studies in other countries are required before generalizing our findings.

In conclusion, this nationwide family study confirmed that, in Taiwan, a family history of CHD is one of the strongest risk factors for CHD. Differential risk associated with different kinships suggested a strong familial component in the susceptibility of CHD. These findings may be useful in counselling families with CHD patients.

Acknowledgments

This work was supported by the National Science Council of Taiwan (project 105-2314-B-182A-135-MY2 and 105-2320-B-182A-007) and Chang Gung Memorial Hospital (Projects CMRPG5F0011, CMRPG3E0651, CMRPG3F08511 and CMRPG3F0831) and was supported by the University of Nottingham in methodology and infrastructure. This study is based in part on National Health Insurance Research Database data provided by the Administration of National Health Insurance, Ministry of Health and Welfare, and managed by the National Health Research Institutes. The interpretation and conclusions contained herein do not represent positions of either the Administration of National Health Insurance or the National Health Research Institutes. We appreciate Wayne Chu and Yuka Chu’s critical reading.

Disclosure of Potential Conflicts of Interest

The authors have no conflict of interest to declare. The authors do hereby declare that all illustrations and figures in the manuscript are entirely original and do not require reprint permission.

Supplementary Files

Supplementary File 1

Table S1. RRs for subtypes of CHD in sibling relatives

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-0250

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