Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration

Lanktree, Matthew B.; Elbers, Clara C.; Li, Yun; Zhang, Guosheng; Duan, Qing; Karczewski, Konrad J.; Guo, Yiran; Tragante, Vinicius; North, Kari E.; Cushman, Mary; Asselbergs, Folkert W.; Wilson, James G.; Lange, Leslie A.; Drenos, Fotios; Reiner, Alex P.; Barnes, Michael R.; Keating, Brendan J.

doi:10.1194/jlr.p059477

Cited by 11 publications

(17 citation statements)

References 25 publications

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“…For comparability with traditional GWAS, we evaluated results from stage 1 main effect models. Of the 356 previously reported associations for 279 variants (compiled from 1–6,12 ), there were 236 associations for 189 variants that were confirmed in our data (consistent direction and p < 0.05/356), for a 66.3% concordance rate (Supplementary Table 17).…”

Section: Resultssupporting

confidence: 86%

Multi-ancestry genome-wide gene–smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids

2019

Nat Genet

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105

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The concentrations of high- and low-density lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 novel loci, some of which were detected only because the association differed by smoking status. Additionally, we demonstrated the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

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Section: Resultssupporting

confidence: 86%

Multi-ancestry genome-wide gene–smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids

2019

Nat Genet

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105

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“…Additionally, when testing replication of SNPs previously identified in groups other than non-Hispanic whites, we generally found that the meta-analysis of all GERA groups provided consistent evidence of replication, and performed better than using the much smaller ancestry-matched group. In the GERA meta-analysis, 2/2 lead SNPs first identified in African Americans 7 , 12 replicated, 4/5 Japanese 11 and Chinese 64 SNPs replicated, and 26/34 SNPs in Mexicans 10 /Hispanics 5 replicated.…”

Section: Discussionmentioning

confidence: 99%

“…For replication of previously-reported loci, we first considered the loci from GLGC 3 , 4 , but favoring the refinements from 20 (when exome-wide significant) and 16 , 18 plus additional novel loci from several studies 5 – 10 , 12 – 15 , 17 , for a total of 189 loci (defined here as non-overlapping 1Mb windows, using the most significant p-value for the lead SNP, and collapsing 1Mb windows with R 2 >0.3, which merged only one window). Of these, 185 were available to test.…”

Section: Methodsmentioning

confidence: 99%

A large electronic-health-record-based genome-wide study of serum lipids

Theusch²,

et al. 2018

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A genome-wide association study of 94,674 multi-ethnic Kaiser Permanente members utilizing 478,866 longitudinal untreated serum lipid electronic-health-record-derived measurements (EHRs) empowered multiple novel findings: 121 new SNP associations (46 primary, 15 conditional, 60 in meta-analysis with Global Lipids Genetic Consortium); increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater in females for LDL, HDL, TC, the opposite for TG); differences in variance explained amongst non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistasis, with strong evidence for both at ABOxFUT2 for LDL; and eQTL tissue-enrichment implicating the liver, adipose, and pancreas. Utilizing EHR pharmacy data, both LDL and TG genetic risk scores (477 SNPs) were strongly predictive of age-at-initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying novel genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease.

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“…Larger genome-wide studies of African ancestry individuals are needed. Additionally, careful consideration of linkage disequilibrium structure differences across ancestries can yield new insights in previously identified regions[87, 93]. …”

Section: Genomic Influences On Interethnic Differences In Serum Lipidsmentioning

confidence: 99%

Interethnic Differences in Serum Lipids and Implications for Cardiometabolic Disease Risk in African Ancestry Populations

Bentley¹,

Rotimi

2017

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African Americans are generally found to have a healthier lipid profile (lower triglycerides [TG] and higher high-density lipoprotein cholesterol concentration [HDLC]) compared to those of other ethnicities. Paradoxically, African Americans do not experience a decreased risk of the cardiometabolic diseases that serum lipids are expected to predict. This review explores this mismatch between biomarker and disease among African ancestry individuals by investigating the presence of interethnic differences in the biological relationships underlying the serum lipids – disease association. This review also discusses the physiologic and genomic factors underlying these interethnic differences. Additionally, because of the importance of serum lipids in assessing disease risk, interethnic differences in serum lipids have implications for identifying African ancestry individuals at risk of cardiometabolic disease. Where possible, data from Africa is included, to further elucidate these ancestral differences in the context of a different environmental background.

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Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration

Abstract: and replication). EXOC3L1 is strongly expressed in vascu-

Cited by 11 publications

References 25 publications

Multi-ancestry genome-wide gene–smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids

Multi-ancestry genome-wide gene–smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids

A large electronic-health-record-based genome-wide study of serum lipids

Interethnic Differences in Serum Lipids and Implications for Cardiometabolic Disease Risk in African Ancestry Populations

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