Category Archives: Genetics

Update on Mendelian Randomization

As written before I never published any study that included a Mendelian randomization. The reasons are well known.

A new paper from Bristol discusses  the  recent explosion of low-quality two-sample Mendelian randomization studies and offers a cure.

We advise editors to simply reject papers that only report 2SMR findings, with no additional supporting evidence. For reviewers receiving such papers, we provide a template for rejection.

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Risks you should be aware of as study participant

I wrote about this about this basically 15 years ago

Confidentiality has been seen in the past as a fundamental ethical principle in health care and breaching confidentiality is usually a reason for disciplinary action. It has been assigned such a great value because it directly originates from the patient’s autonomy to control his or her own life […] Two types of re-identification are possible: the “Netflix” type and the “profiling” type.

There is a new Cell paper that builds a “profiling” attack using even single-cell gene expression data only

we demonstrate that individuals in single-cell gene expression datasets are vulnerable to linking attacks, where attackers can infer their sensitive phenotypic information using publicly available tissue or cell-type-specific expression quantitative trait loci (eQTLs) information.

So this should be included in informed consent forms also.

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The last post here on 23andme

https://www.theatlantic.com/health/archive/2024/09/23andme-dna-data-privacy-sale/680057/

Trusting a private for-profit company with your genetic data was never a good idea.

23andMe is not doing well. Its stock is on the verge of being delisted. It shut down its in-house drug-development unit last month, only the latest in several rounds of layoffs. Last week, the entire board of directors quit, save for Anne Wojcicki, a co-founder and the company’s CEO. Amid this downward spiral, Wojcicki has said she’ll consider selling 23andMe—which means the DNA of 23andMe’s 15 million customers would be up for sale, too

 

30.3.2025

https://bsky.app/profile/adamweinstein.bsky.social/post/3lljqxplhgk22
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4 waves of human ageing

The Guardian writes that humans age dramatically increases in two bursts at 44, then 60 years. The headline may be misleading as it misses the growth spurt in 10 year old children but also the cachexia of people around 90.

The report relies on a report with limited observation period

In this study, we performed comprehensive multi-omics profiling on a longitudinal human cohort of 108 participants, aged between 25 years and 75 years. The participants resided in California, United States, and were tracked for a median period of 1.7 years, with a maximum follow-up duration of 6.8 years.

but nevertheless it confirms my own observation with age effects in bursts around 45 and again in 60 (even did some studies on chronobiology and DNA ageing that confirmed ELOVL2 effects in 2015 while a confirmation study 2020 could not be finished due to COVID19).

It is a bit annoying, however, as there are always different numbers in the Snyder study when compared to earlier reports of the same group  that missed the current findings.

Even worse as there was no a priori  study plan  the results look more like a display of a random data warehouse where you can pick what you waant. So where is the main effect and what is the driving force? The authors are counting significant changes

If we look at the proportional max/min change it is roughly 40% at transcriptomics and proteomics and 32% at metabolomics level. But I have no clue what’s behind these peaks – GTPase activity? Oxygen carrier? As there are no methylation data, no tissue biospy, not even any blood sample covering the whole time span, it remains a rather fuzzy paper that tries to provide a scientific basis of a common sense observation.

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Scopus is broken

was the recent title of a Retraction Watch essay

the problems with the Scopus journal rankings, however, run much deeper. The issue is not that inflated citation numbers have occasionally propelled impostor journals to the top of the list. Rather, at least in my own field of literary studies, the ranking makes no sense whatsoever.

I can confirm that also the h-index calculation is  wrong when looking up my own account – showing 68 instead of 82.

false count by 25/7/24
(probably) true count by 25/7/24

 

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Informed consent for genetic data before 1997

I was involved in a controversy back in 2005 where I opposed the view that

 it should be possible to perform research without informed consent if the samples and data are anonymized or pseudonymized

Glad to see a new correspondence letter in Nature on March 12

since the 1997 UNESCO Universal Declaration on the Human Genome and Human Rights, there has been a clear duty to obtain informed consent for human genetic research. But we did not conclude that human genetic data collected before 1997 were exempt from the need for informed consent. Rather, without recognized international standards, imposing a duty to retroactively obtain consent documentation from data providers is challenging.

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Genetic drivers of heterogeneity

“Genetic drivers of heterogeneity” is the new description for the failed genetic concept of “reverse genetic engineering” – where we see now only sand running through the fingers.

The genetic cause of type II diabetes explodes now into fragments. There are now 1,289 “association signals” in a new study while in another study published back to back in Nature 1 billion new genetic variants are being described that have not been included in the 1289 or 08-15 analysis.
What is the purpose of  counting grains of sand?
And why introducing a new concept of race as noted also by others?

 

27 Feb 2024

Another reaction by Michael Eisen and Ewan Birney

The problem, critics said, is that UMAP creates blobs that look distinct while masking the inherent messiness in the data. “The fact that they are distinct is an artefact/feature of UMAP,” Ewan Birney, director of the European Bioinformatics Institute, wrote in a long thread

and by Lior Pachter who has an analysis way beyond the outrage

We begin with the figure legend, which lists Race, Ethnicity and Ancestry. Race and Ethnicity refer to the self identified race choices for participants (based on the OMB categories). Ancestry refers to the genetic ancestry groups discussed above. While these three concepts are distinct, the Ancestry colors are the same as some of the Race and Ethnicity colors: This is problematic because the coloring suggests a 1-1 identification between certain races and ethnicities, and genetic ancestry groups.

where we indeed arrive now at scientific racism.

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A retro trio study

Nature News writes about a genetic study in Chinese families

The study also identified some new links. For example, mothers with higher levels of bile acid had shorter babies. Clifton says the analysis falls short of establishing causality but offers leads for further research.

I wonder about the title “The Born in Guangzhou Cohort Study enables generational genetic discoveries” which is more promotional than informational. I wonder also about the geopolitical statement as the map includes also Taiwan (with zero observations, as found also in a previous Cell paper). 

And well this is certainly not the first family study in China (see the halted research of Scott Weiss just before he went into vitamin lobbying).

It is also not any new information that mothers with higher levels of bile acid have shorter babies. Did neither interviewer nor interview partner ever hear of intrahepatic cholestasis during pregnancy that is leading to multiple adverse perinatal outcomes?
Cholestasis is leading to preterm birth, which is  leading to LBW (by an OR of 2) and also to shorter babies.  Without any preregistration and any replication study included, it is difficult to make any conclusion of “leads for further research”. The bile acid result may be a regional artifact if it is only found in one region – basically like in the farming studies.

Neither are numbers in this study as large as the Nature News piece wants us to believe,  I think that 332 trios is only an average study size.

 

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Parallelized computer code and DNA transcription

At stackexchange there is a super interesting discussion on parallelized computer code and DNA transcription (which is different to the DNA-based molecular programming literature…)

IF : Transcriptional activator; when present a gene will be transcribed. In general there is no termination of events unless the signal is gone; the program ends only with the death of the cell. So the IF statement is always a part of a loop.

WHILE : Transcriptional repressor; gene will be transcribed until repressor is not present.

FUNCTION: There are no equivalents of function calls. All events happen is the same space and there is always a likelihood of interference. One can argue that organelles can act as a compartment that may have a function like properties but they are highly complex and are not just some kind of input-output devices.

GOTO is always dependent on a condition. This can happen in case of certain network connections such as feedforward loops and branched pathways. For example if there is a signalling pathway like this: A → B → C and there is another connection D → C then if somehow D is activated it will directly affect C, making A and B dispensable.

Of course these are completely different concepts. I fully agree with the further stackexchange discussion that

it is the underlying logic that is important and not the statement construct itself and these examples should not be taken as absolute analogies. It is also to be noted that DNA is just a set of instructions and not really a fully functional entity … However, even being just a code it is comparable to a HLL [high level language] code that has to be compiled to execute its functions. See this post too.

Please forget everything you read from Francis Collins about this.

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Inheritance of facial characteristics

There is a fascinating story from Barcelona. Maybe I missed the NYT article last year but here it is: Cell Reports 40, 111257, August 23, 2022

Joshi et al. reported that look-alike pairs identified by facial recognition algorithms share genotypes but not DNA methylomes and microbiomes.

https://doi.org/10.1016/j.celrep.2022.111257

Based on an earlier study, Continue reading Inheritance of facial characteristics

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Did the Neanderthal hominid suffer from asthma?

Maybe this is a largely irrelevant question –  basically as relevant as building a museum on top of some Neanderthal 1 bones – as we can never reliable predict a complex trait just by genetics and some broken bones.

Already Virchow was wrong  believing that the “Neanderthaler” was a modern human suffering from senility and malformations … Anyway, new research wants to answer this question:

Here we show that of the 51 asthma-associated loci that we surveyed, 39 carry variants that were derived in the Neanderthal lineage. The shared sequences suggest that some asthma variants may have originated from the Neanderthal genome after admixture and subsequent introgression into the Eurasian population. Of note, one variant, rs4742170, previously linked to asthma and childhood wheezing, was shown in a recent study to disrupt glucocorticoid receptor binding to a putative IL33 enhancer, and elevate enhancer activity of this key asthma gene.

Sorry to say that there are now >3000 variants associated with asthma  including at least 354 coding variants while the authors used only 51 loci in their study derived from an outdated 2016 review. So we could already end up writing up a review here but  the paper continues with omissions and misunderstandings

most of the Neanderthal-derived SNPs we identified, including those near the lead variants for the asthma GWAS signals, are in non-coding regions of the gene

Unfortunately we need to be exact here – not just “near” some variants. The SNP rs4742170 that they showed from the EVA database had indeed the T allele in the Vindija Neanderthal

https://bioinf.eva.mpg.de/jbrowse/?loc=9%3A6242936..6242991&tracks=hg19_1000g%2Cvindija_hc_bam%2CAltai

but unfortunately when going then to dbSNP it is also found in the African genome.

https://www.ncbi.nlm.nih.gov/snp/?term=rs4742170

So the whole conclusion

Our findings here …  add asthma to the list of diseases that could be traced back to Neanderthals

is wrong.

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Google Scholar ranking of my co-authors is completely useless

The title says it already while a new r-blogger post helped tremendously to analyze my own scholar account for the first time.

I always wondered how Google Scholar ranked my 474 earlier co-authors. Continue reading Google Scholar ranking of my co-authors is completely useless

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sun + wind + allergy

New work by Harvard colleagues shows how sunshine hormone  D constrains inflammation by modulating the expression of key genes on chr17q. It builds on earlier collaborative work on the vitamin D receptor in 2004 (see their ref 5) as well on my annotation of IKZF3 (aka aiolos aka god of winds) in 2008  and again in 2022.

While our focus on allergy development was on vitamin D supplementation of newborns, the interest of Weiss et al. was on vitamin D deficiency in pregnancy.  Vitamin D deficiency may not be attributed to the rise of the asthma and allergy epidemic although this remains the never ending obsession of Weiss et al.

Nevertheless, also a wrong hypothesis may lead to new insights.  IKZF3 clearly is a key player where more recently heterozygous missense/LOF variants have been found in families with B-lymphopenia and EBV-associated lymphoma while the allergy proning effect is more in the 5-prime region.

The new study shows (again) that cholecalciferol suppresses the activation of the IL-2 pathway. But what is the net effect of artifical cholecalciferol exposure on naive T cells? Unfortunately the  new paper narrowly focuses on cytokine production in Th2 cells only and even misses the famous Cantorna review that clearly says

 Since 1983 it has been described that 1,25(OH)2D inhibited T cell proliferation and the secretion of select cytokines after mitogen stimulation. Moreover, 1,25(OH)2D directly inhibited IL-2 and IFN-γ transcription [,]. More recently 1,25(OH)2D has also been shown to inhibit IL-17 secretion by Th17 cells. The effects of 1,25(OH)2D on Th2 cells is more controversial with evidence that 1,25(OH)2D inhibits IL-4 transcriptionally as well as evidence that 1,25(OH)2D upregulates IL-4 in mouse and human T cells.

So  we need to rephrase the finding of an “immune protective effect of vitamin D in allergic lung inflammation” to an overall “immune suppressive effect of vitamin D” which is basic textbook knowledge. Unfortunately the early origin of allergy induction remains a mystery.

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I never read the introduction of an article

I never read the introduction of an article, seldom the discussion section, but I always scan the methods and sometimes (if the methods warrant it) also the tables and figures. It seems that I am not alone here.

The survey indicated that individuals at different career stages valued different sections of scientific papers, and skill in reading the results section develops slowly over the course of an academic career.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189753

So why do we still write papers with an introduction that is longer than 1 sentence?

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