The impact of evolutionary processes in shaping the genetics of complex traits in East Asia and Europe: a specific contribution from Denisovan and Neanderthal introgression

Koller, Dóra; Wendt, Frank R.; Pathak, Gita A; Lillo, Antonella De; Angelis, Flavio De; Cabrera‐Mendoza, Brenda; Tucci, Serena; Polimanti, Renato

doi:10.1101/2021.08.12.456138

Cited by 4 publications

(4 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S-LDSR can be used with either in-sample LD scores (i.e., computed from the same data as for GWAS) or out-of sample LD scores (i.e., computed from an external and often much smaller data set). Out-of-sample LD scores from 1000 Genomes (1KG) is often used in S-LDSR ( McArthur et al, 2021 ; Koller et al, 2021 ) because (1) it is computationally much cheaper to compute than using the GWAS cohorts, and (2) individual-level data from GWAS cohorts are not always accessible; despite that, S-LDSR with in-sample LD scores is more accurate in theory. Previous studies by Koller et al and McArthur et al used S-LDSR to estimate the heritability from archaic ancestries.…”

Section: Identification Of Snps That Tag Neanderthal Ancestry On the ...mentioning

confidence: 99%

The lingering effects of Neanderthal introgression on human complex traits

Wei

Robles

Pazokitoroudi

et al. 2023

eLife

View full text Add to dashboard Cite

The genetic variants introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed variants. We developed rigorous methods to assess the contribution of introgressed Neanderthal variants to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal variants and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal variants have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.12% of heritable variation averaged across phenotypes). However, the contribution of introgressed variants tends to be significantly depleted relative to modern human variants matched for allele frequency and linkage disequilibrium (about 59% depletion on average), consistent with purifying selection on introgressed variants. Different from previous studies (McArthur 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal variants with 64 phenotypes . Previous work (Skov 2020) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. We therefore developed a customized statistical fine-mapping methodology for introgressed variants that led us to identify 112 regions (at a false discovery proportion of 16%) across 47 phenotypes containing 4,303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveal their substantial impact on genes that are important for the immune system, development, and metabolism. Our results provide the first rigorous basis for understanding how Neanderthal introgression modulates complex trait variation in present-day humans.

show abstract

Section: Identification Of Snps That Tag Neanderthal Ancestry On the ...mentioning

confidence: 99%

The lingering effects of Neanderthal introgression on human complex traits

Wei

Robles

Pazokitoroudi

et al. 2023

eLife

View full text Add to dashboard Cite

show abstract

“…S-LDSR can be used with either in-sample LD scores (i.e., computed from the same data as for GWAS) or out-of sample LD scores (i.e., computed from an external and often much smaller data set). Out-of-sample LD scores from 1000 Genomes (1KG) is often used in S-LDSR (McArthur 2021, Koller 2021) because 1) it is computationally much cheaper to compute than using the GWAS cohorts, and 2) individual-level data from GWAS cohorts are not always accessible; despite that, S-LDSR with in-sample LD scores is more accurate in theory.…”

Section: Supplementary Notesmentioning

confidence: 99%

The lingering effects of Neanderthal introgression on human complex traits

Wei

Robles

Pazokitoroudi³

et al. 2022

Preprint

View full text Add to dashboard Cite

The mutations introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed mutations. We developed rigorous methods to assess the contribution of introgressed Neanderthal mutations to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal mutations and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal mutations have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.1% of heritable variation averaged across phenotypes; p = 9.59×10-9). However, the contribution of introgressed mutations tends to be significantly depleted relative to modern human mutations matched for allele frequency and linkage disequilibrium (about 57% depletion on average), consistent with purifying selection on introgressed mutations. Different from previous studies (McArthur 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal mutations with 64 phenotypes (p < 1 ×10-10). Previous work (Skov 2021) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. We therefore developed a customized statistical fine-mapping methodology for introgressed mutations that led us to identify 112 regions (at a false discovery proportion of 16%) across 47 phenotypes containing 4,303 unique genetic variants where introgressed mutations are highly likely to have a phenotypic effect. Examination of these mutations reveal their substantial impact on genes that are important for the immune system, development, and metabolism. Our results provide the first rigorous basis for understanding how Neanderthal introgression modulates complex trait variation in present-day humans.

show abstract

“…Stratified-LDSC (S-LDSC) was implemented in GenomicSEM for >51 genomic annotations (baseline annotation v2.2 with flanking and continuous annotations excluded) related to allele frequency strata, genomic conservation, evolutionary selective pressure, epigenomic regulatory sites, etc. [17][18][19][20] The major histocompatibility complex region was excluded from these analyses due to its complex linkage disequilibrium structure.…”

Section: Trait Descriptionmentioning

confidence: 99%

Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data

Reis

Newton

Kessler

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Genome-wide association studies (GWAS) of suicidal thoughts and behaviors support the existence of genetic contributions. Continuous measures of psychiatric disorder symptom severity can sometimes model polygenic risk better than binarized definitions. We compared two severity measures of suicidal thoughts and behaviors at the molecular and functional levels using genome-wide data. We used summary association data from GWAS of four traits analyzed in 122,935 individuals of European ancestry:thought life was not worth living(TLNWL),thoughts of self-harm, actual self-harm, andattempted suicide. The fifth trait, suicidality, was constructed with phenotypically as an aggregate of these four traits and genetically using Genomic Structural Equation modeling. Suicidality and S-factor were compared at the level of SNP-heritability (h2), genetic correlation, partitionedh2, effect size distribution, transcriptomic effects in the brain, and cross-population polygenic scoring (PGS). The S-factor had good model fit (χ2=0.21, AIC=16.21, CFI=1.00, SRMR=0.024). Suicidality (h2=7.6%) had higherh2than the S-factor (h2=2.54, Pdiff=4.78×10-13). Although the S-factor had a larger number of non-null susceptibility loci (πc=0.010), these loci had small effect sizes compared to those influencing suicidality (πc=0.005, Pdiff=0.045). Theh2of both traits was enrichment for conserved biological pathways. Therg andρGEsupport highly overlapping genetic and transcriptomic features between suicidality and the S-factor. PGS using European-ancestry SNP effect sizes strongly associated with TLNWL in Admixed Americans: Nagelkerke’sR2=8.56%, P=0.009 (PGSsuicidality) and Nagelkerke’sR2=7.48%, P=0.045 (PGSS-factor). An aggregate suicidality phenotype was statistically more heritable than the S-factor across all analyses and may be more informative for future study genetic designs than individual suicidality indicator traits.

show abstract

The impact of evolutionary processes in shaping the genetics of complex traits in East Asia and Europe: a specific contribution from Denisovan and Neanderthal introgression

Cited by 4 publications

References 100 publications

The lingering effects of Neanderthal introgression on human complex traits

The lingering effects of Neanderthal introgression on human complex traits

The lingering effects of Neanderthal introgression on human complex traits

Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data

Contact Info

Product

Resources

About