Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease

Li, Alexander H.; Morrison, Alanna C.; Kovar, Christie; Cupples, L. Adrienne; Brody, Jennifer A.; Polfus, Linda M.; Yu, Bing; Metcalf, Ginger; Veeraraghavan, Narayanan; Liu, Xiaoming; Lumley, Thomas; Mosley, Thomas H.; Gibbs, Richard A.; Boerwinkle, Eric

doi:10.1038/ng.3270

Cited by 52 publications

(62 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4). Indeed, the finding that TIGIT loss-of-function mutations in humans are associated with dysregulated triglyceride levels suggests that there are additional functions of this protein yet to be elucidated 143 .…”

Section: Tigit and Pvr Family Membersmentioning

confidence: 99%

Combination cancer immunotherapy and new immunomodulatory targets

Mahoney

Rennert²,

Freeman

2015

Nat Rev Drug Discov

1,106

907

View full text Add to dashboard Cite

Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response.

show abstract

Section: Tigit and Pvr Family Membersmentioning

confidence: 99%

Combination cancer immunotherapy and new immunomodulatory targets

Mahoney

Rennert²,

Freeman

2015

Nat Rev Drug Discov

1,106

907

View full text Add to dashboard Cite

show abstract

“…These differences demonstrate the expected allelic heterogeneity underlying rare variant burden signals that traverse populations and highlight the importance of seeking replication at the locus rather than at the constituent variant level. A gene-level meta-analysis of APOC3 burden signals across the exome sequencing study by Crosby et al (9), the MANOLIS WGS finding described here and the exome sequencing study by Li et al (10) using Stouffer’s method yields strong evidence for association with TG levels ( P = 3.23 × 10 − 31 , n = 13 480). Inhibition of apolipoprotein C-III in pre-clinical and clinical studies has been shown to reduce plasma TGs, a major risk factor for cardiovascular disease (15), thereby opening possibilities for new therapeutic routes.…”

Section: Resultsmentioning

confidence: 60%

“…The first, by Crosby et al (9) from the TG and high density lipoprotein (HDL) Working Group of the Exome Sequencing Project, includes two other variants, a missense variant, A43T, in exon 3 (position 116701560), and another splice variant at the donor splice site of intron 3 (position 116701613). The second, by Li et al (10), includes rs140621530, a rare splice donor variant, and the novel singleton frameshift indel 11:116703578. These four variants are all absent from the HELIC-MANOLIS cohort.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, exome sequencing of ∼8500 European American and African American individuals identified a rare LoF variant burden in APOC3 , also associated with TGs (10). Here, we use very low-depth whole-genome sequencing (WGS) data in a Greek isolated population to describe an APOC3 cardioprotective signal missed by genome-wide imputation and to provide empirical proof-of-principle of how very low-depth sequencing can leverage the power advantages afforded by founder populations in catalysing these discoveries.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Very low-depth sequencing in a founder population identifies a cardioprotectiveAPOC3signal missed by genome-wide imputation

et al. 2016

View full text Add to dashboard Cite

Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n = 1239) and find significant evidence for association with blood triglyceride levels with the previously reported R19X cardioprotective null mutation (β = −1.09,σ = 0.163, P = 8.2 × 10−11) and a second loss of function mutation, rs138326449 (β = −1.17,σ = 0.188, P = 1.14 × 10−9). The signal cannot be recapitulated by imputing genome-wide genotype data on a large reference panel of 5122 individuals including 249 with 4x WGS data from the same population. Gene-level meta-analysis with other studies reporting burden signals at APOC3 provides robust evidence for a replicable cardioprotective rare variant aggregation (P = 3.2 × 10−31, n = 13 480).

show abstract

“…Li et al 27 recently reported ten gene-based associations aggregating null variants with a p-value < 4.4 × 10 −6 . Individuals of African Ancestry contributed to seven of these associations.…”

Section: Resultsmentioning

confidence: 99%

Association of Exome Sequences With Cardiovascular Traits Among Blacks in the Jackson Heart Study

Peloso

Lange

Varga

et al. 2016

Circ Cardiovasc Genet

Self Cite

View full text Add to dashboard Cite

Background The correlation of null alleles with human phenotypes can provide insight into gene function in humans. In individuals of African ancestry, we set out to identify null and damaging missense variants, and test these variants for association with a range of cardiovascular phenotypes. Methods and Results We performed whole exome sequencing in 3,223 African American individuals from the Jackson Heart Study and found a total of 729,666 variant sites with minor allele frequency (MAF) < 5%, including 17,263 null variants and 49,929 missense variants predicted to be damaging by in silico algorithms. We tested null and damaging missense variants within each gene for association with 36 cardiovascular traits. We found three associations that met our pre-specified level of significance (α=1.1×10−7). Null and damaging missense variants in PCSK9 were associated with 36 mg/dl lower low density lipoprotein cholesterol (LDL-C) (p-value=3×10−21). Three individuals in their 50s with complete PCSK9 deficiency (each compound heterozygote for PCSK9 p.Y142X and p.C679X) were identified, with one having a coronary artery calcification score in the 83rd-percentile despite a LDL-C of 32 mg/dl. A damaging missense variant in HBQ1 (p.G52A) was associated with a 2 pg/cell lower mean corpuscular hemoglobin (p-value=9×10−13) and rare damaging missense variants in VPS13A with higher red blood cell distribution width (p-value=9.9 × 10−8). Conclusions A limited number of null/damaging alleles with a large effect on cardiovascular traits were detectable in ~3,000 African American individuals.

show abstract

Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease

Cited by 52 publications

References 25 publications

Combination cancer immunotherapy and new immunomodulatory targets

Combination cancer immunotherapy and new immunomodulatory targets

Very low-depth sequencing in a founder population identifies a cardioprotectiveAPOC3signal missed by genome-wide imputation

Association of Exome Sequences With Cardiovascular Traits Among Blacks in the Jackson Heart Study

Contact Info

Product

Resources

About