Sasha Gusev
@sashagusevposts.bsky.social
Statistical geneticist. Associate Prof at Dana-Farber / Harvard Medical School.
www.gusevlab.org
www.gusevlab.org
Reposted by Sasha Gusev
Excited to share a preprint of my PhD project looking at interactions between SNPs and polygenic scores in the UK Biobank!
A thread... 🧵
www.medrxiv.org/content/10.1...
A thread... 🧵
www.medrxiv.org/content/10.1...
Interactions with polygenic background impact quantitative traits in the UK Biobank
Association studies have linked many genetic variants to a variety of phenotypes but under-standing the biological mechanisms underlying these signals remains a major challenge. Since genes operate wi...
www.medrxiv.org
November 24, 2025 at 5:13 PM
Excited to share a preprint of my PhD project looking at interactions between SNPs and polygenic scores in the UK Biobank!
A thread... 🧵
www.medrxiv.org/content/10.1...
A thread... 🧵
www.medrxiv.org/content/10.1...
When non-genetic, correlative analyses are shown to be genetically confounded, the lesson is that we shouldn't use them to draw any causal conclusions.
When genetic analyses are shown to be environmentally confounded the lesson is, uh, look, they just estimate different parameters okay!
When genetic analyses are shown to be environmentally confounded the lesson is, uh, look, they just estimate different parameters okay!
I didn’t inhibit my argueing muscle enough. this is actually the right take, it’s eventually a case of “what’s your estimand?”. And it’s all observational, though it needs rigorous models before you can get to an answer (which can be, “these aren’t comparable ever”)
SNP h2 is not even h2 and even with we assume all these to be true, it all breaks up when there's selection and drift.
November 24, 2025 at 2:29 PM
When non-genetic, correlative analyses are shown to be genetically confounded, the lesson is that we shouldn't use them to draw any causal conclusions.
When genetic analyses are shown to be environmentally confounded the lesson is, uh, look, they just estimate different parameters okay!
When genetic analyses are shown to be environmentally confounded the lesson is, uh, look, they just estimate different parameters okay!
Reposted by Sasha Gusev
Some history of science grad student is going to have one hell of a dissertation about how Arthur Jensen wrecked two disciplines for half a century.
November 21, 2025 at 11:53 PM
Some history of science grad student is going to have one hell of a dissertation about how Arthur Jensen wrecked two disciplines for half a century.
I wrote a little bit about the "missing heritability" question and several recent studies that have brought it to a close. A short 🧵
The missing heritability question is now (mostly) answered
Not with a bang but with a whimper
theinfinitesimal.substack.com
November 21, 2025 at 10:34 PM
I wrote a little bit about the "missing heritability" question and several recent studies that have brought it to a close. A short 🧵
Nice! Whole-genome heritability estimates in the UK Biobank. Average WGS-h2 was 26%, with 21% common and 5% rare. Broadly aligns with recent sib-reg and RDR estimates.
First time on Bsky and first big announcement!
I am excited to announce that our new study explaining the missing heritability of many phenotypes using WGS data from ~347,000 UK Biobank participants has just been published in @Nature.
Our manuscript is here: www.nature.com/articles/s41....
I am excited to announce that our new study explaining the missing heritability of many phenotypes using WGS data from ~347,000 UK Biobank participants has just been published in @Nature.
Our manuscript is here: www.nature.com/articles/s41....
Estimation and mapping of the missing heritability of human phenotypes - Nature
WGS data were used from 347,630 individuals with European ancestry in the UK Biobank to obtain high-precision estimates of coding and non-coding rare variant heritability for 34 co...
www.nature.com
November 13, 2025 at 11:41 PM
Nice! Whole-genome heritability estimates in the UK Biobank. Average WGS-h2 was 26%, with 21% common and 5% rare. Broadly aligns with recent sib-reg and RDR estimates.
Reposted by Sasha Gusev
Excited to share this preprint from first author Jon Rosen, a postdoctoral fellow in the @klmohlke.bsky.social lab and my lab. We examine eQTL study sample size and how this affects signal discovery and rates of colocalization with GWAS.
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
Higher eQTL power reveals signals that boost GWAS colocalization
Expression quantitative trait locus (eQTL) studies in human cohorts typically detect at least one regulatory signal per gene, and have been proposed as a way to explain mechanisms of genetic liability...
www.biorxiv.org
August 18, 2025 at 12:18 PM
Excited to share this preprint from first author Jon Rosen, a postdoctoral fellow in the @klmohlke.bsky.social lab and my lab. We examine eQTL study sample size and how this affects signal discovery and rates of colocalization with GWAS.
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
Reposted by Sasha Gusev
Very happy to be back in Boston for #ASHG25🧬 this time as a PI! Very proud of my stellar PhD student Jiawei who’s giving a platform talk on her work quantifying influences of genetic ancestry and the environment on tumor somatic alterations and survival.
🗓️ Wed Oct 15 11:15AM
🗓️ Wed Oct 15 11:15AM
October 14, 2025 at 5:32 PM
Very happy to be back in Boston for #ASHG25🧬 this time as a PI! Very proud of my stellar PhD student Jiawei who’s giving a platform talk on her work quantifying influences of genetic ancestry and the environment on tumor somatic alterations and survival.
🗓️ Wed Oct 15 11:15AM
🗓️ Wed Oct 15 11:15AM
Reposted by Sasha Gusev
In 2018, Charles Murray challenged me to a bet: "We will understand IQ genetically—I think most of the picture will have been filled in by 2025—there will still be blanks—but we’ll know basically what’s going on." It's now 2025, and I claim a win. I write about it in The Atlantic.
Your Genes Are Simply Not Enough to Explain How Smart You Are
Seven years ago, I took a bet with Charles Murray about whether we’d basically understand the genetics of intelligence by now.
www.theatlantic.com
October 13, 2025 at 1:33 PM
In 2018, Charles Murray challenged me to a bet: "We will understand IQ genetically—I think most of the picture will have been filled in by 2025—there will still be blanks—but we’ll know basically what’s going on." It's now 2025, and I claim a win. I write about it in The Atlantic.
Massive sibling regression study finds that human traits are largely environmentally driven (average heritability = 0.3)
Within-family heritability estimates for behavioural and disease phenotypes from 500,000 sibling pairs of diverse ancestries
Quantification of the direct effect of genetic variation on human behavioural traits is important for understanding between-individual variation in socio-economic and health outcomes but estimates of ...
www.medrxiv.org
September 20, 2025 at 6:19 PM
Massive sibling regression study finds that human traits are largely environmentally driven (average heritability = 0.3)
Interesting evidence for genetics explaining disparities in T2D. Previous work identified a Neanderthal introgressed haplotype common to Native American ancestry with a large effect on T2D (pmc.ncbi.nlm.nih.gov/articles/PMC...). Wonder if there's power to look at archaic admixture here.
Brilliant paper by Visscher et al.
Populations differ in traits/disease burden. Are these differences due to genetics?
Comparing single variants or polygenic scores between populations is biased due to environmental confounders correlated with the variants.
1/3
www.medrxiv.org/content/10.1...
Populations differ in traits/disease burden. Are these differences due to genetics?
Comparing single variants or polygenic scores between populations is biased due to environmental confounders correlated with the variants.
1/3
www.medrxiv.org/content/10.1...
Direct effect of genetic ancestry on complex traits in a Mexican population
Human populations differ in disease prevalences and in average values of phenotypes, but the extent to which differences are caused by genetic or environmental factors is unknown for most complex trai...
www.medrxiv.org
September 11, 2025 at 5:55 PM
Interesting evidence for genetics explaining disparities in T2D. Previous work identified a Neanderthal introgressed haplotype common to Native American ancestry with a large effect on T2D (pmc.ncbi.nlm.nih.gov/articles/PMC...). Wonder if there's power to look at archaic admixture here.
Reposted by Sasha Gusev
Brilliant paper by Visscher et al.
Populations differ in traits/disease burden. Are these differences due to genetics?
Comparing single variants or polygenic scores between populations is biased due to environmental confounders correlated with the variants.
1/3
www.medrxiv.org/content/10.1...
Populations differ in traits/disease burden. Are these differences due to genetics?
Comparing single variants or polygenic scores between populations is biased due to environmental confounders correlated with the variants.
1/3
www.medrxiv.org/content/10.1...
Direct effect of genetic ancestry on complex traits in a Mexican population
Human populations differ in disease prevalences and in average values of phenotypes, but the extent to which differences are caused by genetic or environmental factors is unknown for most complex trai...
www.medrxiv.org
September 11, 2025 at 5:57 AM
Brilliant paper by Visscher et al.
Populations differ in traits/disease burden. Are these differences due to genetics?
Comparing single variants or polygenic scores between populations is biased due to environmental confounders correlated with the variants.
1/3
www.medrxiv.org/content/10.1...
Populations differ in traits/disease burden. Are these differences due to genetics?
Comparing single variants or polygenic scores between populations is biased due to environmental confounders correlated with the variants.
1/3
www.medrxiv.org/content/10.1...
Reposted by Sasha Gusev
Delighted to see this paper with @anaignatieva.bsky.social now published in Genetics!
academic.oup.com/genetics/adv...
We tackle a thorny issue arising in statistical tests for genetic interactions (epistasis) using ancestral recombination graphs (ARGs)... 🧵
academic.oup.com/genetics/adv...
We tackle a thorny issue arising in statistical tests for genetic interactions (epistasis) using ancestral recombination graphs (ARGs)... 🧵
Phantom epistasis through the lens of genealogies
Abstract. Phantom epistasis arises when, in the course of testing for gene-by-gene interactions, the omission of a causal variant with a purely additive ef
academic.oup.com
September 10, 2025 at 4:31 PM
Delighted to see this paper with @anaignatieva.bsky.social now published in Genetics!
academic.oup.com/genetics/adv...
We tackle a thorny issue arising in statistical tests for genetic interactions (epistasis) using ancestral recombination graphs (ARGs)... 🧵
academic.oup.com/genetics/adv...
We tackle a thorny issue arising in statistical tests for genetic interactions (epistasis) using ancestral recombination graphs (ARGs)... 🧵
Reposted by Sasha Gusev
Excited to share our latest manuscript, "Exposure accumulation drives age-dependent disease architectures and polygenic risk scores," led by Xilin Jiang: www.medrxiv.org/content/10.1...
I am attempting an explainer thread for the first time here:
(I am usually too exhausted to post one)
I am attempting an explainer thread for the first time here:
(I am usually too exhausted to post one)
Exposure accumulation drives age-dependent disease architectures and polygenic risk scores
Our understanding of the dependence of the genetic and environmental architecture of common diseases on age is incomplete. Here, we use longitudinal data to quantify age-dependent genetic and environm...
www.medrxiv.org
September 2, 2025 at 11:08 PM
Excited to share our latest manuscript, "Exposure accumulation drives age-dependent disease architectures and polygenic risk scores," led by Xilin Jiang: www.medrxiv.org/content/10.1...
I am attempting an explainer thread for the first time here:
(I am usually too exhausted to post one)
I am attempting an explainer thread for the first time here:
(I am usually too exhausted to post one)
Reposted by Sasha Gusev
I wrote about a rare genetic variant (a CNV) that appears to reduce the risk of schizophrenia diagnosis by ~5x, and why that's not as unambigously amazing as it sounds, but potentially still a pretty big deal.
Its probably nothing, but if it is...
A rare copy number variant appears to significantly reduce the risk of schizophrenia.
open.substack.com
September 2, 2025 at 2:14 PM
I wrote about a rare genetic variant (a CNV) that appears to reduce the risk of schizophrenia diagnosis by ~5x, and why that's not as unambigously amazing as it sounds, but potentially still a pretty big deal.
Great mini thread here on lessons for GxG and GxE from non-human organisms:
Nice blog and good to see this also from the twins/shared environment side. We (with my colleagues in @wittbrodtlab.bsky.social) have tried to tackle the non-additive in experimental settings (in medaka fish) which we can map to human (as the medaka fish are "wild") www.biorxiv.org/content/10.1...
Discovery and characterisation of gene by environment and epistatic genetic effects in a vertebrate model
Phenotypic variation arises from the interplay between genetic and environmental factors. However, disentangling these interactions for complex traits remains challenging in observational cohorts such...
www.biorxiv.org
August 29, 2025 at 12:09 AM
Great mini thread here on lessons for GxG and GxE from non-human organisms:
Reposted by Sasha Gusev
Nice blog and good to see this also from the twins/shared environment side. We (with my colleagues in @wittbrodtlab.bsky.social) have tried to tackle the non-additive in experimental settings (in medaka fish) which we can map to human (as the medaka fish are "wild") www.biorxiv.org/content/10.1...
Discovery and characterisation of gene by environment and epistatic genetic effects in a vertebrate model
Phenotypic variation arises from the interplay between genetic and environmental factors. However, disentangling these interactions for complex traits remains challenging in observational cohorts such...
www.biorxiv.org
August 28, 2025 at 3:10 PM
Nice blog and good to see this also from the twins/shared environment side. We (with my colleagues in @wittbrodtlab.bsky.social) have tried to tackle the non-additive in experimental settings (in medaka fish) which we can map to human (as the medaka fish are "wild") www.biorxiv.org/content/10.1...
Reposted by Sasha Gusev
🧵 on cool choices of image headers (and titles) all from @sashagusevposts.bsky.social's Substack
🔗 at the end
'Beneath the surface of the sum'
Genetic interactions may look like the thing they deviate from
Interaction (1964) by Julian Stanczak
🔗 at the end
'Beneath the surface of the sum'
Genetic interactions may look like the thing they deviate from
Interaction (1964) by Julian Stanczak
August 28, 2025 at 8:00 AM
🧵 on cool choices of image headers (and titles) all from @sashagusevposts.bsky.social's Substack
🔗 at the end
'Beneath the surface of the sum'
Genetic interactions may look like the thing they deviate from
Interaction (1964) by Julian Stanczak
🔗 at the end
'Beneath the surface of the sum'
Genetic interactions may look like the thing they deviate from
Interaction (1964) by Julian Stanczak
I wrote about gene-gene interactions (epistasis) and the implications for heritability, trait definitions, natural selection, and therapeutic interventions. Biology is clearly full of causal interactions, so why don't we see them in the data? A 🧵:
Beneath the surface of the sum
When genetic interactions matter and when they don't
open.substack.com
August 27, 2025 at 8:41 PM
I wrote about gene-gene interactions (epistasis) and the implications for heritability, trait definitions, natural selection, and therapeutic interventions. Biology is clearly full of causal interactions, so why don't we see them in the data? A 🧵:
Reposted by Sasha Gusev
The twin/family studies were not clear whether it was dominance vs. epistasis vs. some other sort of nonadditivity. Dominance was just the easiest to model. We can now estimate dominance SNP h2 but can’t obtain an estimate of epistatic SNP h2. Assimilation/contrast effects may also be at play.
August 18, 2025 at 12:26 AM
The twin/family studies were not clear whether it was dominance vs. epistasis vs. some other sort of nonadditivity. Dominance was just the easiest to model. We can now estimate dominance SNP h2 but can’t obtain an estimate of epistatic SNP h2. Assimilation/contrast effects may also be at play.
Reposted by Sasha Gusev
While I am not entirely convinced this is “real” and not some psychometric equivalent of a vowel shift (and PRS could help find out a bit I think) this it is relevant:
August 17, 2025 at 7:11 PM
While I am not entirely convinced this is “real” and not some psychometric equivalent of a vowel shift (and PRS could help find out a bit I think) this it is relevant:
One of the largest twin studies of personality anticipated massive non-additive dominance/epistasis components. These have not materialized with modern data for *any trait*, no one knows why, and the entire set of findings has apparently been memory-holed.
August 17, 2025 at 6:34 PM
One of the largest twin studies of personality anticipated massive non-additive dominance/epistasis components. These have not materialized with modern data for *any trait*, no one knows why, and the entire set of findings has apparently been memory-holed.
Decrease in phenotype by intervening on additive or epistatic mechanisms in the presence of low (left) or high (right) epistasis. Red lines indicate an increase in the phenotype when a decrease was intended.
August 12, 2025 at 9:25 PM
Decrease in phenotype by intervening on additive or epistatic mechanisms in the presence of low (left) or high (right) epistasis. Red lines indicate an increase in the phenotype when a decrease was intended.
Reposted by Sasha Gusev
Popgen, day7: single-locus selection models. Allele frequency change is faster at intermediate frequencies! Fixation takes longer in larger pops! And a bit more from yesterday on MK (asymptotic MK test is cool!)
August 12, 2025 at 6:58 PM
Popgen, day7: single-locus selection models. Allele frequency change is faster at intermediate frequencies! Fixation takes longer in larger pops! And a bit more from yesterday on MK (asymptotic MK test is cool!)
Any discussion of embryo selection should probably start with the description of IVF in this piece, to at least be connected to some aspect of tangiable reality.
August 11, 2025 at 11:44 PM
Any discussion of embryo selection should probably start with the description of IVF in this piece, to at least be connected to some aspect of tangiable reality.