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 Table of Contents  
Year : 2019  |  Volume : 3  |  Issue : 4  |  Page : 235-242

Carrier rate analysis of single-gene disorders based on 1000 genome project and exome aggregation consortium data

Laboratory of Medical Foods, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

Date of Submission16-May-2019
Date of Web Publication2-Jan-2020

Correspondence Address:
Hua-Jun Zheng
No. 2140, Xietu Road, Xuhui District, Shanghai 200032
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.274546

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Objective: Screening variants underlying the single-gene disorder in the general population can help reduce the incidences of birth defects. To determine the most prevalent pathogenic variants causing autosomal recessive diseases, we investigated the frequencies of these variants in six major geographic ancestry groups from Exome Aggregation Consortium (ExAC) database and 26 populations from the 1,000 Genome Project, including three Chinese ethnic groups.
Methods: We selected 64 autosomal recessive diseases and collected corresponding causal genes and variants from ClinVar for the analysis. The RS (reference single-nucleotide polymorphism) IDs of these variants were used to search the corresponding VCF file from the 1,000 Genomes Project and ExAC databases. We calculated the frequencies of heterozygotes of each disease variants in the 1,000 Genomes Project and ExAC samples and compared the distribution of disease alleles among different populations.
Results: Our analysis revealed that 1,151/212 variants were carried by 60,706/2,504 individuals sequenced in the ExAC/1,000 Genomes Project. The average number of autosomal recessive disease alleles carried by samples from ExAC and 1,000 Genomes Project were 0.53 and 0.68, respectively. These disease alleles showed differential distribution among populations, and some disease alleles were significantly enriched in certain ethnic groups. In addition, 1–2 main pathogenic variants were identified in each disease. Meanwhile, several ClinVar variants with relatively high frequency (>1%) in the samples were found to be benign instead of “conflicting evaluations of pathogenicity.”
Conclusions: Our observations revealed that main pathogenic variants existed in certain autosomal recessive disease, suggesting that screening of disease hypermutations in different populations is valuable in reducing the occurrence of birth defects.

Keywords: Single-Gene Disorders; Exome Aggregation Consortium; 1,000 Genomes Project; Carrier Rate

How to cite this article:
Duan MM, Zheng HJ. Carrier rate analysis of single-gene disorders based on 1000 genome project and exome aggregation consortium data. Reprod Dev Med 2019;3:235-42

How to cite this URL:
Duan MM, Zheng HJ. Carrier rate analysis of single-gene disorders based on 1000 genome project and exome aggregation consortium data. Reprod Dev Med [serial online] 2019 [cited 2020 Apr 1];3:235-42. Available from: http://www.repdevmed.org/text.asp?2019/3/4/235/274546

  Introduction Top

There are currently more than 7,000 known rare diseases,[1] including albinism, Gaucher's disease, and pulmonary cystic fibrosis (CF). The prevalence of rare diseases is less than 1/2,000,[2] and 80% are genetic diseases.[3] Single-gene disorders are genetic diseases caused by a single or a pair of mutational alleles on homologous chromosomes, also known as Mendelian diseases. If a healthy couple carries the same recessive variant, their offspring have a 25% chance of having the disease. These diseases can be devastating, and there are currently no effective treatments, which exerts considerable pressure on families and society. Therefore, it is necessary to carry out carrier screening for such single-gene disorders. Screening carriers with normal phenotypes in the population by adopting economical, accurate, and reliable methods would help risk assessment and marriage and childbirth guidance and would help prevent birth defects.

Carrier screening is of great significance in preventing birth defects. Tay–Sachs disease (TSD), an autosomal recessive disorder with stunting, blindness, and epilepsy, is a progressive disease with low survival rates after 4 years and which is highly prevalent in the Jewish (especially German Jewish) population.[4] There is currently no effective treatment for this disease. In the 1970s, California launched statewide TSD screening.[5] After 30 years of hard work, the incidence of TSD in the Jewish population in the United States,[6] Canada,[7] and Israel decreased by 90%.[8] In addition, CF carrier screening is performed routinely on the majority of sperm donor applicants in the United States.[9] Screening of pregnant women and newborns at risk for sickle cell disease in Italy also proved necessary for the early diagnosis.[10]

High-throughput sequencing techniques can detect genetic diseases, both in diagnosis and in finding new or rare variants,[11],[12],[13],[14] thus it can be used for carrier screening. The National Health Commission of China announced 121 rare diseases in 2018, including 64 autosomal recessive diseases. In this study, the carrier rates of variants involving these 64 autosomal recessive diseases were analyzed based on the data from the 1000 Genomes Project, which provides a global reference for human genetic variation through reconstructing the genomes of 2,504 individuals from 26 populations.[15] Exome sequence data from 60,706 individuals in the Exome Aggregation Consortium (ExAC) were also used to validate our analysis results.[16]

  Methods Top

Data set

We downloaded the VCF file of the Phase 3 release of the 1,000 Genomes Project from its website (http://www.internationalgenome.org/), which contained 84.7 million variants involving 2,504 individuals from 26 populations worldwide. Among them, 105 individuals were Southern Han Chinese, 93 were Chinese Dai from Xishuangbanna, and 103 were Han Chinese from Beijing. VCF file of 60,706 human exomes (Release 1.0) was downloaded from ExAC Browser Beta (http://exac.broadinstitute.org/), which included high-quality variant sites of individuals corresponding to Finnish, non-Finnish European, African, South Asian, East Asian, and admixed American (Latino) ancestry.

Analysis procedures

We selected 64 autosomal recessive diseases from 121 rare diseases that are regarded as common in China. The genes and variants associated with these 64 diseases were then collected from ClinVar.[17] The RS (reference single-nucleotide polymorphism [SNP]) IDs of the disease-causing variants found in ClinVar were then used to search the corresponding VCF file of the 1,000 Genomes Project and ExAC, respectively. Then, the frequencies of heterozygotes of each disease variants in the 1,000 Genomes Project and ExAC population were calculated [Figure 1]. The 95% confidence intervals of carrier rate of single-gene disorders were estimated based on a normal approximate method using the following formula:
Figure 1: Strategy for carrier rate statistics for autosomal recessive diseases using the data of ExAC and 1,000 Genomes Project.

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P: Probability; Zα/2: Critical value; SP: Sampling error; n: Sample size, where Zα/2 = 1.96 when α = 0.05.

Enrichment of autosomal recessive diseases for each ethnic group was calculated using a classical hypergeometric distribution statistical comparison of the disease carrier rate in each ethnic group against the disease carrier rate in 2,504 individuals or 60,706 individuals. The calculated P values underwent the false discovery rate (FDR) correction, taking a corrected P < 0.05 as a threshold. Diseases fulfilling this condition were defined as significantly enriched in each ethnic group.

Data availability

The variant sites associated with the 64 autosomal recessive diseases can be downloaded from ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh37/.

  Results Top

Mutated genes and sites associated with autosomal recessive diseases

Sixty-four autosomal recessive diseases regarded as common in China were selected in our analysis. Searching the ClinVar database revealed 319 genes associated with these diseases, including 2,712 variant sites [Supplementary Table 1]. Some diseases, such as biotinidase deficiency (BTD), had 145 known associated variant sites, whereas sickle cell disease had only two.

Percapita carrier rates of variants associated with autosomal recessive diseases

Carrier rates of the 2,712 variants associated with the 64 autosomal recessive diseases were analyzed in the 2,504 individuals, and a total of 276 variants were identified. After excluding benign variants, we found that 212 (7.8%) pathogenic, likely pathogenic or conflicting interpretations of pathogenicity variants associated with 50 (78.1%) of diseases were carried by the 2,504 individuals, with an average of 0.68 variant sites per individual [Supplementary Table 2].

In ExAC, a total of 1,574 variants were identified in 60,706 individuals. After excluding benign variants, we found that 1,132 (41.7%) pathogenic, likely pathogenic or conflicting interpretations of pathogenicity variants associated with 63 (98.4%) of diseases were carried by the 60,706 individuals, with an average of 0.53 variant sites per individual [Supplementary Table 3].

Some conflicting interpretations of pathogenicity in ClinVar may cause erroneous classification and statistics, and hence, we deleted conflicting interpretations of pathogenicity before further statistical analysis.

Of the 64 diseases, 14 had no associated variants in the 26 populations investigated, including arginase deficiency (13 variants), lysinuric protein intolerance (7 variants), tetrahydrobiopterin deficiency (6 variants), congenital adrenal hypoplasia (32 variants), hypophosphatemic rickets (24 variants), idiopathic hypogonadotropic hypogonadism (12 variants), Silver– Russell syndrome More Details (7 variants), and Wiskott-Aldrich syndrome (17 variants). This might result from the low carrier rate of these diseases in the population, with the low prevalence of 1/2,000,000,[18] 1/60,000,[19] 1/500,000–1/1,000,000,[20] 1/140,000–1/1,200,000,[21] 1/20,000,[22] 1–10/100,000,[23] 1/30,000–1/100,000,[24] and 1/100,000–1/1,000,000,[25] respectively. In ExAC, variants associated with Silver–Russell syndrome were not revealed, further indicating its low carrier rate in the population.

Population differences in carrier rates

The number of variants carried by different populations was different. Among them, the per capita number of variants in the three populations of Chinese Dai, Han in Beijing, and Southern China was 0.44, 0.67, and 0.60, respectively.

There were significant population and regional differences in the risk and carrier rates of different hereditary diseases. As we can see, the disease exhibiting the highest carrier rate in six major geographic ancestry groups differed from each other [Table 1]. For example, BTD exhibited the highest carrier rates in South Asian (2.75%). This was supported by the 1000 Genome Project data [Table 2], which showed that BTD exhibited the highest carrier rates in the four populations of South Asian, varying from 1.96% in Indian Telugu in the UK to 5.88% in Sri Lankan Tamils in the UK (FDR <0.05, meaning BTD carriers were significantly enriched in Indian Telugu in the UK). BTD is an inherited metabolic disorder of biotin (Vitamin B) recycling that leads to multiple carboxylase deficiencies. According to OrphaNet, a data source on rare diseases,[26] the prevalence of BTD is estimated to be 1/61,000, and the carrier frequency in the general population is approximately 1/120.
Table 1: Single-gene diseases with the highest carrier rates in six major geographic ancestry groups

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Table 2: Single-gene diseases with the highest carrier rates in 26 ethnic groups

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Other diseases showing higher carrier frequency included progressive familial intrahepatic cholestasis (PFIC), with a carrier frequency of 14.14% in Luhya in Webuye, Kenya, and 4.67% carrier frequency in the Iberian populations in Spain (both populations showed a significant enrichment of PFIC, with FDR < 0.05). PFIC refers to a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin, with an estimated incidence between 1/50,000 and 1/100,000 births.[27] CF carriers have been reported to be more common in Europe and America,[28] and our analysis revealed that 4.81% of Japanese from Tokyo are at risk for this disease [Table 2].

Collectively, these data showed that genetic diseases with high carrier rates varied across different ethnic groups.

We further analyzed diseases with a high carrier rate in Asia. BTD is the most commonly carried diseases in four populations of South Asia, whereas the five populations of East Asia exhibited high carrier rates of different genetic disorders [Table 3]. Carnitine deficiency is a disease exhibiting the highest carrier rate (2.15%) in Chinese Dai in Xishuangbanna. The disease with the highest carrier rate in Han Chinese in Beijing is Parkinson Disease (Young-onset, Early-onset, 3.88%), and in Southern Han Chinese is nonsyndromic deafness (2.86%). However, no autosomal recessive diseases displayed significant enrichment in the Chinese populations, while both Kallmann syndrome and pulmonary CF showed significant enrichment in Japanese in Tokyo, Japan [Table 3].
Table 3: Carrier rates of different single-gene diseases in the Asian populations

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Single-gene diseases are mainly caused by 1–2 pathogenic variants in populations

Although each autosomal recessive disease has 2–145 different gene variant sites, only one or two hypermutations were observed in the populations studied [Figure 2]. Among the 212 variants carried by the 26 ethnic groups, carrier rates of 55 variants involving 31 genetic diseases were >0.1% in the 2,504 individuals, and ten variants of six genetic diseases were hypermutations with a carrier rate >1% [Figure 3]. Then, in the ExAC data, eight of the 10 variants also showed a carrier rate >1% [Table 4]. It can be seen from [Table 5] that several genetic diseases are mainly caused by 1–2 pathogenic variants. For example, over half of BTD carriers have a variant involving rs397514333, and carriers of PFIC have a variant affecting rs45575636.
Figure 2: Number of pathogenic variants in different single-gene diseases. 212 pathogenic variants were carried by 2,504 individuals in the 1,000 Genomes Project. The blue bars correspond to the ratio of these variants relative to known variants associated with the disease.

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Figure 3: Variant carrier rates. Among the 2,712 variants, the population carried 212 (7.8%) variants, of which 10 variants involving 6 genetic diseases were carried in more than 1% of the population.

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Table 4: Ten hypermutations with carrier rates >1% in populations

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Table 5: Main SNP contributing to single-sgene diseases and carrier rates in different populations

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These genetic diseases are mainly caused by 1–2 SNP variants, and thus, the hypermutation of genetic diseases can be selected as a target in disease carrier screening, which can greatly reduce costs and ensure effective screening.

High carrier rates versus low prevalence validate conflicting evaluations of pathogenicity

In ClinVar, specific standard terminology such as “pathogenic,” “likely pathogenic” and “benign” were used to interpret clinical significance of each variant,[29] with “likely pathogenic” defined as >90% certainty of a variant being disease-causing. However, interpretation of the same variant by multiple clinical laboratories may differ,[30] and result in a clinical significance as “conflicting interpretations of pathogenicity.”

It has been reported that some of the variants in ClinVar have either low penetrance or inaccurate pathogenicity assignment, and a large proportion of the variants with conflicting clinical significance are benign.[31]

Of the 2,712 variants deposited in ClinVar, 1,151 variants involving 63 diseases were revealed in the individuals of the 1,000 Genomes Project and ExAC. By analyzing the carrier rate of these variants, we found that the carrier rate of 10 variants was >1% [Table 4]. rs1126809, a variant causing albinism, has a population carrier rate of 13.62% in the 1,000 Genome Project and 30.99% in ExAc. The prevalence of all forms of albinism has been estimated at approximately 1/17,000,[32] so such a high carrier rate is unreasonable if we compare the calculated disease risk (1/215 if population carrier rate is 13.62%) with the disease prevalence (1/17,000). Although the clinical significance of rs1126809 in ClinVar is “conflicting interpretations of pathogenicity,” we were able to validate that it is a benign variation.

Similarly, the carrier rates of several other variants listed in [Table 4] are strikingly high, indicating possible incorrect classifications in ClinVar. Because most of these variation sites with high carrier rates are deposited in ClinVar with no clinical evidence, our analysis provided a robust validation that these variant sites are indeed benign.

  Discussion Top

The birth defect ratio is consistently increasing due to environmental factors and increased childbearing age. China's population determines that it is a country with a high birth-defect burden. These birth defects include 21-hydroxylase deficiency,[33] albinism,[34] Kallmann syndrome,[35] and mitochondrial encephalomyopathy.[36] These diseases are currently not well treated, and the patient's family and society bear a heavy burden. Through the statistical analysis, we identified that each individual, on an average, carries 0.53–0.68 pathogenic variants involving recessive genetic diseases and that each population has a different risk of developing specific autosomal recessive diseases. If a couple carry the same variant site of a certain recessive genetic disease, the chance that their child will have the disease is 25%. Hence, the higher carrier rate of recessive genetic diseases associated variants in certain ethnic group means higher disease prevalence in this population. Therefore, it is necessary to screen these genetic carriers to provide childbirth guidance and to prevent the birth of defective infants.

The carrier rates among different ethnic groups were different, and the genetic diseases involved were mainly caused by 1–2 variants. Therefore, we selected variants with a high frequency in different genetic diseases to screen according to ethnic differences. Genetic diseases with high carrier rates included BTD, albinism, and nonsyndromic deafness [Table 2]. Because the high carrier rate of each disease is usually caused by one or two pathogenic variants, high-throughput screening for common autosomal recessive diseases is feasible.

An important factor hampering genetic screening is cost. CRISPR Cas-12a technology and mass arrays can be used for the detection of a small number of variants (like the 100 main variant sites associated with 64 autosomal recessive diseases in China).[37] Cas-12a identifies SNPs by forming a Cas12a/crRNA/target DNA ternary complex that cleaves nonspecific fluorescently labeled ssDNA probes.[38],[39] Massarrays, developed by Agena Bioscience,[40],[41] amplify the target sequence through PCR, adds an SNP sequence-specific extension primer and extends 1 base at the SNP site. The precise molecular weight of the sample analyte is obtained by detecting the time of flight of the nucleic acid molecule in a vacuum tube and thereby SNP locus information is obtained. Both platforms have the following advantages: high accuracy, high throughput, easy operation, flexibility, and cost-effectiveness.

The key step to screen genetic variant sites is to select the most important variant site for each disease. The 1,000 Genome Project and ExAC provided us with valuable information. We used these data to obtain the carrier rates of recessive genetic diseases in different populations and determined the hypermutation of each disease in each population. Based on regional and population differences, high-risk genetic diseases in various geographical locations were identified, and targeted screening for carriers could be carried out to reduce the incidence of birth defects.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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