Round-up Nov 11 – Dec 21


  • The major news was the report of the birth of the first children genetically modified as embryos. I report on that separately here.
  • The question of whether those who receive a genetic diagnosis have a duty to tell their family members is working its way through the UK courts. A man who received a genetic diagnosis of Huntington’s asked the hospital not to tell his daughter, who was pregnant at the time, because he feared she would abort the baby. The daughter has since been found to have the genetic variant associated with Huntington’s is now suing the hospital. Bioethicist Anna Middleton told the Guardian “This could really change the way we do medicine, because it is about the duty that doctors have to share genetic test results with relatives and whether the duty exists in law.”
  • UCL launched an inquiry into their past ties with eugenics, including to Galton. This was motivated by a series of secretive eugenics meetings that an academic of theirs was recently involved with.


  • PsychENCODE, a large consortium looking at functional genomics in over 2000 developing and adult brains, has published 10 papers. To focus on one paper, they found that differences in gene expression between individuals are mostly explained by differences in fractions of cell types, and that some disorders and aging are associated with changes in these proportions. For schizophrenia, they found 321 genes associated with GWAS loci, and then did some fancy machine learning to predict phenotype from genotypes and from expression. This model did much better than a genotype polygenic score alone, and still did better when the expression data was imputed (i.e. not actually experimentally measured), “highlighting the value of having just a small amount of transcriptome data for disease prediction.”
  • Large study of the genetics of ADHD finds reproducible loci. A polygenic score predicts 5.5% of the variance (for an odds ratio of 1.56). The study presents evidence that ADHD should be considered the end of a distribution: “Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.”
  • A much smaller fraction of developmental disorders (DDs) are explained by recessive variation in protein-coding genes than previously thought: ~3.6% in non-consanguineous populations, compared to 31% in consanguineous populations. Compare to 50% of DDs caused by de novo mutations. This work, from Hilary Martin et al appearing in Science, is based on a burden analysis approach in over 6000 exomes from the Deciphering Developmental Disorders study. “The high proportion of unexplained patients even amongst those with affected siblings or high consanguinity suggests that future studies should investigate a wide range of modes of inheritance including oligogenic and polygenic inheritance as well as noncoding recessive variants.”
  • “Just thinking you have poor endurance genes changes your body” – individuals were told a test had revealed they had one or another version of the gene CREB1, which affects how easily one tires, and were then set to run on a treadmill. Those who were told they had the version would meant they would tire more easily did indeed tire more easily. In fact, the participants had been randomized. Likewise for FTO, which can affect how full you feel, participants who were told they had the “less hungry” version of the gene reported feeling less hungry, and had higher levels of a hormone associated with feeling full. This would be a type of placebo effect for genetic information: “The results suggest that if a person just thinks they are at high risk for, say, obesity, it could change their physiology in a way that makes them more prone to the condition, Turnwald says.” (Paper here). “If simply conveying genetic risk information can alter actual risk, clinicians and ethicists should wrestle with appropriate thresholds for when revealing genetic risk is warranted.”
  • Calico and have teamed up to show that longevity is <10% genetic. Using a single pedigree of over 400 million individuals, they were able to show that previous estimates (about 15-30%) overestimated genetic inheritance because they were confounded by non-genetic inheritance showing up via the effects of assortative mating.
  • Mitochondria can be inherited from both parents in humans. The inheritance appears to be autosomal.
  • We’ve known for a long time that there is a lot of undiscovered genetic diversity in African populations, and that use of the reference genome is rife with problems. Sequencing of 910 African genomes has showed just how large the problem is: at least 10% of reads failed to align to the reference genome, but were alignable to constructed pan-African contigs.
  • A polygenic score for schizophrenia explained some of the variance in response to antipsychotics.
  • In a severe reminder that polygenic scores cannot be used in ancestral populations not included in their construction, also using the polygenic score for schizophrenia from the Psychiatric Genetics Consortium, it was shown that the mean difference between Europeans and Africans was ten times as great as the mean difference between the European cases and controls.
  • I missed this in my last round-up. At ASHG researchers in GeneRisk, from Finland, presented data on over 7000 individuals who were given cardiac risk information, some including their polygenic cardiac risk score. Those identified at higher risk, particularly if genetic, did well at making lifestyle changes.
  • Mendelian Randomization is the idea that because genetics at birth is randomized and not altered by environmental confounders, considering some gene X, one can see whether gene X is subject to Loss or Gain of Function variants in the disease of interest. If it is, then Gene X is s good drug candidate – many high cost drug trials could have been avoided if MR had been performed. The technique can also be used to distinguish between correlation and causation, for example in showing that the correlation between obesity and depression is at least partially explained by obesity causing depression (depression odds ratio of 1.18 for 1 SD higher genetic risk score for high BMI). There are many improvements to the most basic MR model, see e.g. correcting for genetic correlations with shared etiology.
  • As an alternative to Mendelian Randomization posted to bioarxix, BADGERS (Biobank-wide Association Discovery using GEnetic Risk Scores), designed to identify associations between a disease and hundreds to thousands genetically-predicted complex traits (using polygenic scores). Variants can be reclassified.
  • A study has shown that over 30% of patients had their variants reclassified within a five year time period. “The findings of this study suggest that pediatric patients with epilepsy and previous genomic test results should have their test results reinterpreted at least every 2 years and before further genetic testing.”
  • A nice review of the genetic variation relevant to immunotherapy, written by one of my former colleagues, Eric Kofman.



  • The UN’s Convention on Biological Diversity considered, and rejected, a ban on gene drives. Both those working on gene drive technology and those campaigning against it called the result a win. They state the need for informed consent, but it is not clear what this means: “who gets to decide when the African people have consented — and how unanimous a decision you need when millions of lives are on the line”
  • China has cracked down on companies that have sequenced Chinese individuals and then exported the data. Adam Minter argues that this view of chinese genetic data as a national security matter is in keeping with other chinese policies on e.g. the internet. Ultimately, a lack of openness will damage science, and chinese science in particular.
  • In April 2018 the FDA issued guidance on the use of databases in genomic testing. Applying that guidance, they have approved use of ClinGen’s Expert Curated Human Genetic Data as clinical evidence in approval submissions for tests. The data covers over 10,000 variants (ClinVar review status (“reviewed by expert panel”or “practice guideline”).
  • LunaDNA received SEC approval to sell shares to customers, part of its business plan to incentivize individuals to share their genomic data. It currently values a whole genome at $21.

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