ASHG 2024 - Day 2

Yixuan He

Multi-trait multi-ancestry association analysis revealed new loci and improved PRS for comorbid traits related to lung. COPD, lung cancer, asthma, FEV, FVC, etc. PRSxtra captures ancestry-specific information across diverse populations and genetic information from multiple related traits at the SNP level.

Preprint: 10.1101/2024.08.25.24312558

Ozvan Bocher

T2D is a global and heterogeneous disease, associated with 1,289 index variants! Which genes and proteins are causally associated? They performed 2-sample MR, significance assessed on IVW (independent eQTL or pQTL). No evidence of pleiotropy, no heterogeneity. Discovery on eQTLgen and replication on AFR (GENOA AA) and AMR (GALAII). They found 81 genes and 5 proteins causal to T2D with little heterogeneity. 14 genes and 6 proteins are detected in only non-EUR populations.

Yuchang Wu

X-PIGEON: quantifying gene-population effects. PIGEON framework includes the gene-environment interactions using multiple regression. Inputs for X-PIGEON: Genome-wide interaction summary statistics (Robust to LD and allele frequency differences!) and meta-analysis summary statistics. They applied their method to continuous traits with available EAS and EUR GWAS summary statistics.

The audience think that SNPs can be core causal and marginally causal, the first one would not vary much across populations but the second one would.

Wenbo Wang

Large-scale multi-ancestry whole genome sequencing studies

TOPMed: over 200k WGS from ancestrally diverse samples with more than 1m PASS variants. Freeze 8 has N=150000 samples.

Based on genetics similarity, they identify individuals with four genetic ancestry pops: African, East Asian, European and Admixed.

The Ancestry-Informed (AI) framework. Inputs: Genotypes, Covariates. GLM for unrelated and related individuals.

Observed allelic effect sizes correlated with ancestry: heterogeneity in allele freq, LD and environmental factors. Apply ensemble test (Yu et al).

Weighting can be applied to single variants (AI-GWA) and variant sets (AI-STAAR).

They applied AI to TOPMed Freeze 8 kidney function data. AI-GWA increases power. They discover 3 new variant-trait associations for UACR, another 3 new variants for eGFR.

Abram Kamiza

Cervical cancer

Annually, more than 520k women are diagnosed with cervical cancer. HPV infection is the main risk factor. GWAS have identified genetic loci associated with cervical cancer. They conducted GWAS in the black South Africa women.

Johannesburg Cancer Study (JCS). 1,742 cases, total 2,218 controls. For multi-ancestry, they used UKBB, FinnGen and Biobank Japan. They identified five loci associated with cervical cancer in JCS, and 16 loci in the meta-analysis. Out of the 5 loci in JCS, four are new. The strong peak in chr6 appears in other populations as well. In the multi-ancestry analysis, they found 6 novel loci.

Fine-mapping identified loci with posterior probability > 99%.

They developed PRS for JCS as target cohort, 50% used for developing and 50% for validation. Summary data from other cohorts were also used for the PRS. Multi-ancestry PRS performed better than others.

Nayane S. Brito Silva

MHC region has the highest number of associations for infectious and autoimmune diseases in GWAS. They transformed a SNP-based association to HLA allele-based association. SHLARC. SNP-HLA Reference consortium.

They trained HIBAG software on SNP + HLA data to create a reference panel. Across all populations, the accuracy of all reference panels consistently exceeded 90% for most evaluated genes. The errors were mostly related to low-frequency HLA-DRB1 alleles.

Emma Wilson

Muscle eQTL meta-analysis identified 20,253 signals for 13,093 genes.

Also see, T2D heterogeneity: https://doi.org/10.1038/s41586-024-07019-6

Robert Warmerdam

eQTLGen phase 2 uncover additional disease variant–gene links. Phase 2 identified 58,956 trans-eQTLs compared to 19,351 in phase 1. Replicated approximately 1000 eQTLs in OneK1K blood samples (6 tissues). Many hub variants show enrichment for transcription factor activity. Trans-eQTLs closer to GWAS hits, often colocalize with complex traits. This time, they are testing all SNP-gene pairs.

Hope Tanudisastro

Tandem repeats are understudied in population genetics. TenK10K Phase 1 has ~2000 individuals, WGS genotype and scRNA sequencing.