Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South ...Asians, a GPS to identify high-risk individuals may be particularly useful in this population.
This analysis used summary statistics from a prior genome-wide association study to derive a new GPS
for South Asians.
This GPS
was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPS
reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPS
reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.
The GPS
, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPS
distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each).
The new GPS
has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.
Genome-wide polygenic scores are a new approach to quantify inherited risk for a given disease using information from many common sites of DNA variation. The predictive capacity of a polygenic score ...for coronary artery disease in South Asians - a population that suffers from coronary artery disease at significantly higher rates - is largely unknown. Here, we build a polygenic score consisting of over 6.6 million common DNA variants and a workflow for ancestry-corrected risk quantification. Results confirm striking and consistent relationships with coronary artery disease in South Asian populations from the United Kingdom, Bangladesh, and India.
Familial hypercholesterolemia (FH), an autosomal codominant disorder characterized by very high low-density lipoprotein cholesterol, is strongly associated with premature coronary artery disease.
...Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their lives, and cascade screening in their relatives.
Potential cases of FH (n = 100) were identified by criteria adapted for the Indian population from Dutch Lipid Clinic Network criteria. Pathogenic variants were analyzed in LDLR, APOB 100 (exons 26 and 29), PCSK9, and APOE genes using Sanger sequencing and multiplex ligation-dependent probe amplification technique. Cases in whom there were no pathogenic variants were tested by next-generation sequencing using a targeted panel of genes.
Thirty-eight pathogenic variants were identified in 47 of 100 unrelated probands. Of these variants, 33 were identified in LDLR, 3 in APOB, and 2 in PCSK9 genes. Ten pathogenic variants were novel. Mutations were detected in 91.4% of those subjects classified as definite, 40% as probable, and in 18.8% as possible FH cases based on modified Dutch Lipid Clinic Network criteria. A likely founder mutation in intron 10 (c.1587-1G>A) of LDLR gene was observed in 6 North Indian families. The conventional pathogenic variants in APOB and PCSK9 genes and those previously reported in LDLR gene among Asian Indians were not detected in this cohort.
This study demonstrates genetic heterogeneity of FH in India. The variants observed were different from those described in Western populations. Next-generation sequencing technology helped identify new mutations in APOB gene, suggesting that in less-studied populations, it is better to sequence the whole gene rather than test for specific mutations.
•There is paucity of data on genetic studies of FH in Asian Indians.•100 unrelated cases with clinical suspicion of FH classified using modified DLCN.•Sanger sequencing of LDLR, PCSK9, 2 fragments of ApoB, and targeted lipid panel by NGS.•38 different disease-causing mutations (10 novel) identified in 47 unrelated cases.•Mutations identified in the study not reported before in Indians.
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