Genetic and functional evidence relates a missense variant in<i>B4GALT1</i>to lower LDL-C and fibrinogen

Montasser, May E.; Hout, Cristopher V. Van; McFarland, Rebecca; Rosenberg, Avraham; Callaway, Myrasol; Shen, Biao; Li, Ning; Daly, Thomas J.; Howard, Alicia; Lin, Wei Yu; Yuan, Man; Ye, Bin; Gatta, Giusy Della; Tzoneva, Gannie; Perry, James A.; Ryan, Kathleen A.; Miloscio, Lawrence; Economides, Aris N.; Program, Nhlbi TOPMed; Sztalryd-Woodle, Carole; Mitchell, Braxton D.; Healy, Matthew D.; Streeten, Elizabeth A.; Zaghloul, Norann A.; Taylor, Simeon I.; O’Connell, Jeffrey R.; Shuldiner, Alan R.

doi:10.1101/721704

Cited by 4 publications

(4 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The full list of heritability estimates of the 355 lipid species with and without adjustment for 4 Amish-enriched large effect lipid variants ( APOB _rs5742904 7 , APOC3 _rs76353203 8 , B4GALT1 _rs551564683 9 , TIMD4 _rs898956003 10 ) (4 variants) is provided in Supp Table 2. Figure 1a shows that the heritabilities range between 0 and 0.7, with significant attenuation when adjusting for the 4 variants as they account for a significant proportion of the phenotypic variance.…”

Section: Resultsmentioning

confidence: 99%

“…To measure the proportion of lipidomic and traditional lipid variance due to genetic markers associated with HDL, LDL, TC and TG lipid levels, genetic relatedness matrices (GRM) were constructed using SNPs identified from the literature as being genome-wide significant for each lipid plus known Amish-specific variants ( APOB _rs5742904 7 , APOC3 _rs76353203 8 , B4GALT1 _rs551564683 9 , TIMD4 _rs898956003 10 ) (4 variants). The number of literature SNPs used were 99 for HDL, 77 for LDL, 97 for TC, and 73 for TG.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Leveraging a founder population to identify novel rare-population genetic determinants of lipidome

Montasser

Aslibekyan

Srinivasasainagendra

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and new insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of novel biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a GWAS of 355 lipid species in 650 individuals from the Old Order Amish founder population including 127 lipid species not previously tested. We report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants: APOB_rs5742904 and APOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus including GLPTD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus on chromosome 2 and estriol with SLC22A8/A24 locus on chromosome 11. Our results show the power of founder populations to discover novel biology due to genetic drift that can increase an allele found in only a few subjects in even large samples such as UKBiobank to dozens in even samples as small as 650.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Leveraging a founder population to identify novel rare-population genetic determinants of lipidome

Montasser

Aslibekyan

Srinivasasainagendra

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…SNP and INDEL variants and genotypes were called using GATK's HaplotypeCaller. QC metrics were applied as previously described (Montasser et al, 2019). Project‐level and sample‐level VCFs for downstream analyses were generated as the pipeline output.…”

Section: Methodsmentioning

confidence: 99%

The burden of pathogenic variants in clinically actionable genes in a founder population

Lynch

Maloney

Pollin

et al. 2021

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Founder populations may be enriched with certain genetic variants of high clinical impact compared to nonfounder populations due to bottleneck events and genetic drift. Using exome sequencing (ES), we quantified the load of pathogenic variants that may be clinically actionable in 6136 apparently healthy adults living in the Lancaster, PA Old Order Amish settlement. We focused on variants in 78 genes deemed clinically actionable by the American College of Medical Genetics and Genomics (ACMG) or Geisinger's MyCode Health Initiative. ES revealed 3191 total variants among these genes including 480 nonsynonymous variants. After quality control and filtering, we applied the ACMG/AMP guidelines for variant interpretation and classified seven variants, across seven genes, as either pathogenic or likely pathogenic. Through genetic drift, all seven variants, are highly enriched in the Amish compared to nonfounder populations. In total, 14.7% of Lancaster Amish individuals carry at least one of these variants, largely explained by the 13% who harbor a copy of a single variant in APOB. Other studies report combined frequencies of pathogenic/likely pathogenic (P/LP) variants in actionable genes between 2.0% and 6.2% in outbred populations. The Amish population harbors fewer actionable variants compared to similarly characterized nonfounder populations but have a higher frequency of each variant identified, offering opportunities for efficient and cost‐effective targeted precision medicine.

show abstract

“…Exome Sequencing, Variant Calling, and Quality Control DNA samples from 6,809 SWAI individuals were exome sequenced at the Regeneron Genetics Center via sequencing methodology, genome alignment, and genotype calling approaches as previously described. 40 Briefly, exonic regions were targeted with an xGEN probe library with additional capture probes. Targeted DNA was sequenced on the Illumina HiSeq 2500 platform with v4 chemistry with 75bp paired-end reads.…”

Section: Study Subjectsmentioning

confidence: 99%

Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US

Kim

Gosalia

et al. 2020

The American Journal of Human Genetics

Self Cite

View full text Add to dashboard Cite

Applying exome sequencing to populations with unique genetic architecture has the potential to reveal novel genes and variants associated with traits and diseases. We sequenced and analyzed the exomes of 6,716 individuals from a Southwestern American Indian (SWAI) population with well-characterized metabolic traits. We found that the SWAI population has distinct allelic architecture compared to populations of European and East Asian ancestry, and there were many predicted loss-of-function (pLOF) and nonsynonymous variants that were highly enriched or private in the SWAI population. We used pLOF and nonsynonymous variants in the SWAI population to evaluate gene-burden associations of candidate genes from European genome-wide association studies (GWASs) for type 2 diabetes, body mass index, and four major plasma lipids. We found 19 significant gene-burden associations for 11 genes, providing additional evidence for prioritizing candidate effector genes of GWAS signals. Interestingly, these associations were mainly driven by pLOF and nonsynonymous variants that are unique or highly enriched in the SWAI population. Particularly, we found four pLOF or nonsynonymous variants in APOB, APOE, PCSK9, and TM6SF2 that are private or enriched in the SWAI population and associated with lowdensity lipoprotein (LDL) cholesterol levels. Their large estimated effects on LDL cholesterol levels suggest strong impacts on protein function and potential clinical implications of these variants in cardiovascular health. In summary, our study illustrates the utility and potential of exome sequencing in genetically unique populations, such as the SWAI population, to prioritize candidate effector genes within GWAS loci and to find additional variants in known disease genes with potential clinical impact.

show abstract

Genetic and functional evidence relates a missense variant inB4GALT1to lower LDL-C and fibrinogen

Cited by 4 publications

References 48 publications

Leveraging a founder population to identify novel rare-population genetic determinants of lipidome

Leveraging a founder population to identify novel rare-population genetic determinants of lipidome

The burden of pathogenic variants in clinically actionable genes in a founder population

Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US

Contact Info

Product

Resources

About