Analysis of clinically relevant variants from ancestrally diverse Asian genomes

Abstract

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.

Fig. 1. Spectrum of pathogenic variation in clinically relevant genes among Singaporeans.

a Carrier frequencies of ACMG SF v3.0 genes associated with dominant disorders compared across the three main ancestry groups. The disorders are further sub-classified into three main disease domains for comparison (cancer, cardiovascular, lipid disorders). Carrier frequency of P/LP variants in lipid disorder genes were significantly higher among Chinese compared to Indians (p = 7.93 × 10⁻⁵) and Malays (p = 1.70 × 10⁻³). Statistical significance was evaluated by two-sided Fisher’s exact test, with Benjamini-Hochberg correction for multiple testing. Adjusted p < 0.05 was considered significant, ns: not significant. CH: Chinese, IND: Indian, MY: Malay. b Differential distribution of carrier frequencies across ancestries for dominantly inherited genetic disorders associated with ACMG SF v3.0 medically actionable genes, or non-ACMG SF v3.0 genes with a carrier frequency >0.5%. c Genes of recessive conditions with significant differences in carrier frequency of P/LP variants across ancestry groups. Colour scale maps to row-wise z-scores, obtained by subtracting from each gene-level carrier frequency the row average and then dividing the value by the row standard deviation. Genes in red fonts are recommended by ACMG for carrier screening. Genes in bold fonts are part of the ACMG SF v3.0 list. The disorder domain associated with pathogenic alteration of the indicated gene is represented in the dot matrix. CVD cardiovascular disorders, Derm dermatological disorders, Metab. metabolic (including lysosomal storage, mitochondrial, metabolic disorders), Gastro-HPB gastro-hepato-pancreato biliary disorders, Haem/Immuno haematological/immunological disorders, MCA multiple congenital anomalies, Neuro neurological (including neurologic, neuromuscular, neurodegenerative disorders), Others: including cancer, respiratory, genitourinary disorders.

Fig. 2. Evaluating the influence of genetic admixture and potentially pathogenic VUS in SG10K_Health cohort.

a ADMIXTURE analysis of inferred genetic ancestral components at K = 3 juxtaposed with self-reported ancestry for the 9,051 Singaporean individuals. NA: not available. b The proportion of genetic ancestral components tracked consistently with carrier status of pathogenic/likely pathogenic (P/LP) variants specific to the associated ancestry group across Singaporean Chinese (CH), Indian (IND) and Malay (MY) individuals (Chinese-specific variant carriers/non-carriers: (CH) 455/5047, (IND) 2/1939, (MY) 26/1582; Indian-specific variant carriers/non-carriers: (CH) 3/5499, (IND) 147/1794, (MY) 19/1589; Malay-specific variant carriers/non-carriers: (CH) 2/5500, (IND) 2/1939, (MY) 24/1584). Pairwise differences between carriers and non-carriers were evaluated by two-sided Wilcoxon rank-sum test. p < 0.05 was considered significant. ns: not significant. c Juxtaposition of P/LP variants with potentially pathogenic variants of uncertain significance (missense and cryptic splice variants) classified as VUS-FP, identified in genes from the ACMG SF v3.0 list. Mode of inheritance and disease domain associated for each gene are indicated in the dot matrix below. PTV: protein-truncating variant. d Carriers of VUS-FP variants (n = 5) identified in LDLR demonstrated LDL cholesterol range that is consistent with carriers of P/LP variants (n = 25) and is higher compared to non-carriers (n = 4397). An LDL cholesterol level of ≥4.1 mmol/L is classified as high by the Ministry of Health Singapore. p values were derived from binomial logistic regression comparing LDL cholesterol levels against LDLR variant status, correcting for age, sex, genetic ancestry, and lipid-lowering medication intake. All box plots extend from the 25th to 75th percentiles and the length of the whiskers are defined as follows: upper whisker =  min(maximum_value, Q3 + 1.5*IQR), lower whisker = max(mininum_value, Q1–1.5*IQR), where IQR is interquartile range, Q3 is third quartile, Q1 is first quartile. Horizontal line in the box represents the median.

Fig. 3. Carriers of both germline pathogenic/likely pathogenic (P/LP) variant in a CDC Tier 1 condition and pharmacogenetic variant associated with an actionable phenotype to drugs used for treatment.

Only pharmacogenetic variant-drug combinations supported by PharmGKB Level 1A/1B evidence were considered. HBOC hereditary breast and ovarian cancer syndrome, LS Lynch syndrome, FH familial hypercholesterolemia, n number of germline P/LP variant carriers for the indicated CDC Tier 1 genetic conditions among 9051 Singaporeans.