Tag Archives: Population + Epidemiology

Are genes becoming more important with increasing age?

I found an apparent paradox between two studies. John Whitfield did a twin study in Australia and concluded that shared environmental effects decreased with age (from about 50% to 10%) while additive genetic effects increased. The new Sardinian study found higher heritabilities among younger individuals and explained that by an increase of environmental insults with age. Nice said, but who is right?

Sleep well

Just came to my attention that there is research of sleep related genes, the usual stuff of protein kinases, dopaminergic receptor, and serotonine transporter. Also this research community seem to have the common difficulty of the complex disease gene mappers – to understand a phenomenon (not a trait) as systemic function, an intrinsic property of a multicellular and multiwired brain, yea, yea.

Addendum

More strange phenotypes orgasm frequency, pain, human memory performance.

Addendum

Read also the what-we-could-have-learned-from-linkage-studies.

Do not run after a cart that will not take you

Starting with another African proverb, here are some thoughts about evolution, design and the difference of chimps and humans. Yes, I am biased, I know.

I have learned that there are mainly three differences between chimps and human – the ability to run, a larger brain size and the language/speech capability. The only trait that can directly observed is the ability to run (check Munich marathon: Neither brain size and language can be directly observed :-) BTW, I renember having seen a family that walk on feet and hands – quadrupedal locomotion is a recessive trait linked to chromosome 17p, the way we all start our lifes).

So genetics is playing a big role in the human < -> ape differentiation. Or did the differentation select the genes?

You will understand my great expectations when now reading one of the first serious papers about the chimp and the human lineage. It is about pseudogenization, the gene loss during separation of species. The authors show 80 non-processed pseudogenes inactivated in the human lineage – while gently negelecting the fact of another 7868 or so pseudogenes in the human pseudogene database.

There is also nothing about my favorite trait bipedalism (only a ridiculous quote of pseudogenization of the sarcomeric myosin gene MYH16 that should relate to hominin masticatory muscles that “may have allowed the brain size expansion”, uhhh. It is also hard to understand how gain of ability should be caused by loss of gene function, yea, yea.

Dr. Livingstone, I presume?

Asthma in Africa: I will touch this issue in more detail in a forthcoming editorial in PLos Medicine. Africa has fascinated me since childhood when I read books of Paul White, Albert Schweitzer and tried to get everything our library had about David Livingstone and Morton Stanley. Here is a further link that we couldn’t place in the editorial – a 2 month helicopter trip from Hamburg to Kapstadt including daily GPS data to watch a heli flying in Google Earth, simply the best, I have seen in the internet this year, yea.

Are randomized clinical trials gold standard?

A new paper in the Deutsche Ärzteblatt argues that there should be alternatives to RCTs. The reasons are manifold

  • selection bias towards more severely ill patients
  • selection towards too homogeneous samples
  • patients may decline participation
  • physician may decline participation
  • bias towards larger cities and universities
  • usually “hard” endpoints that ignore quality of life, compliance, side effects
  • usually only short time studies
  • protocol may deviate from daily practice in medical routine

Community-based studies may therefore not be as bad, yea, yea.

Addendum

An extended and reworked version of this blog can be found in issue 45 of the “Deutsche Ärzteblatt“, page A3019, 10th November 2006.

Genetic archaeology

While doing a study of European population stratification, I came across an older but interesting study of old testament priests that compares the Levi tribe (where Moses was a member) with the Cohanim tribe (descendents of Moses’s brother Aaron who served as priests). The investigators traced patrilineal inheritance since the temple period 3,000 -2,000 years until present, and showed current levites unlike the Cohanin having a heterogeneous origin. The coalescence of of Cohanim chromosomes is dated to between Exodus and the destruction of the first temple in 586 BC.

Most current research is dedicated to between species comparisons but unfortunately the wonderful older Y and mtDNA approaches haven´t kept pace with the current SNP technology developement. There would be many intersting studies possible following the timeline of European history, yea, yea.

Allelic specific expression

This topic has fascinated me since I read the Pastinen paper from the Hudson group (with updates in Science and Hum Mol Gen; the field probably started with the Yan paper). We had even written a DFG grant application that was not funded.

ASE uses a rather simple principle where the allelic ratio of a heterocygous SNP within a RNA transcript is taken as a measure of gene expression from the different chromosomes (that are carrying either the one or the other SNP allele). A ratio of 0.5 indicates equal expression and becomes distorted if a gene on one chromosome is imprinted or silenced by another way. The ratio can be rather easily determined by MALDI-TOF genotyping of cDNA by pooling protocols. I wonder why this hasn´t been more used as it is probably a more precise measurement than the artificially “self-normalized” expression ratios in classical gene-expression profiling (as Fan pointed out recently).

ASE seems to be much more common than I thought: 53% of all genes showed allele expression differences in at least one individual. Having such a screening instrument at hand, it could even help to clear our SNP genotyping lists. Yea, yea.

More about parents and self

I would be interested to learn more about the rate of non-matching parent-child SNP assays (preferably Affymetrix technology as current Illumina chips do not include low MAF variants).

This could tell us something about the role of de novo somatic mutations: Read more in a recent TIGS paper by Kenneth Weiss. Has anyone checked different tissues of the same individual and looked for mosaics? Or traced the fate of blood transfusions? Or followed up a single individuals over a couple of years?

This idea is also fuelled by a recent Cell paper that shows Sticker’s sarcoma to be transmitted among dogs by licking or biting tumor-affected areas. Yea, yea.

Nylenna-Simonsen-Chalmers Misconduct Diagram

The Lancet (10 June 2006, p 1882) had one of the best descriptions of scientific misconduct that I have ever seen (yes, I am also admiring Geoffrey Rose). The authors argue that our current view of misconduction is wrong those caught for fraud being a few “bad apples”. Instead we are facing a continuum ranging from honest and inevitable errors to outright fraud. I agree up to here, however, I do not believe so much in a “slippery slope” – in my experience the intentional selection of certain entry and exit levels is more common.

Here is my expansion of the original N-S-C diagram:
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Addendum 22 Nov 2020

Bigger is better

John Todd has always been advocating that we should use larger sample sizes in our genetic association studies. I agree, it is also true that larger sample sizes will lead to smaller p-values. In his recent nature genetics comment he now suggest a p of less than 10 up minus 8 to be relevant. Yes, all of his 6 examples show that significance level but only 1 provides functional evidence (the SLE study). All other studies including Todd`s own studies are number-crunchers. I fear that in the absence of functional data 10-8 may not even be sufficient. Think of 500,000 SNPs, 20 possible traits, 5 genetic models and 20 competing groups – this multiplies to 10-9. Interestingly, the SLE study, showed a p of 10-16! Having good functional evidence I would be even willing to accept 10-2. May I point you to an excellent study describing a new rSNP by means of CHIP and expression analysis of de Gobbi – using just a couple of families. Yea, yea.

Time bomb – revisited

I revisited a 2005 paper on “Folic acid – vitamin and panacea or genetic genetic time bomb“. From the abstract: “We live in a health-conscious age — many of us supplement our diet with essential micronutrients … so-called ‘functional foods’ … We examine this issue in relation to the B-group vitamin folic acid, and ask whether supplementation with this vitamin could introduce a strong genetic selection pressure…” As I found this paper highly interesting, here is my analysis, how the story goes on:

  1. Martinez-Frias, ML. Folic acid: a public-health challenge. LANCET.
  2. Kafadar, AM. C677T gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) in meningiomas and high-grade gliomas. ANTICANCER RESEARCH.
  3. Kelemen, LE. The role of folate receptor alpha in cancer development, progression and treatment: Cause, consequence or innocent bystander?. INTERNATIONAL JOURNAL OF CANCER.
  4. Nazarenko, MS. Frequencies of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene at the early stage of human development. RUSSIAN JOURNAL OF GENETICS.
  5. Ferguson, LR. Nutrigenomics – Integrating genomic approaches into nutrition research. MOLECULAR DIAGNOSIS & THERAPY.
  6. Soloway, PD. Gene nutrient interactions and evolution. NUTRITION REVIEWS.
  7. Eichholzer, M.. Folic acid: a public-health challenge. LANCET.
  8. Houghton, LA. [6S]-5-Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. AMERICAN JOURNAL OF CLINICAL NUTRITION.
  9. Ejarque, I. A bioinformatic approach to epigenetic susceptibility in non-disjunctional diseases. BIOLOGICAL AND MEDICAL DATA ANALYSIS, PROCEEDINGS.
  10. Sweeney, MR. Evidence of unmetabolised folic acid in cord blood of newborn and serum of 4-day-old infants. BRITISH JOURNAL OF NUTRITION.
  11. Lucock, MD. The antifolate activity of tea catechins. CANCER RESEARCH.
  12. Kelemen, LE. Multivitamin and alcohol intake and folate receptor alpha expression in ovarian cancer. CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION.
  13. Allegrucci, C. Human embryonic stem cells as a model for nutritional programming: An evaluation. REPRODUCTIVE TOXICOLOGY.

Supersize me and the fake food hypothesis

Is there any sense of genetic studies aiming at an association with body mass index? Will there ever be a public health strategy or any medical intervention based on a genetic marker?
I am recalling what Christoph – a friend of mine at medical school and a now professor for child psychiatry – once told me when he was working on his thesis about anorexia: “You only need to weight them for a diagnosis”. As there are now lots of weighing machines out there, there are plenty of DNAs (intended for different outcomes!), which might be a reason of the 5946 “obesity and gene” papers.
Will this help anybody? I fear, that responsibility is even shifted to “poor genes” (of course I acknowledge that there might be gene nutrient interactions – Paul Soloway wrote a nice essay on that). My view – developed with my wife over many years – is that that the obesity epidemics is largely an environmental trait of poor eating habits, wrong orientation on dress models and not enough physical activity. I recall also Professor Walter Willett – who has been my former advisor in Nutritional Epidemiology – that things can be quite simple. Check for his “Low Glycemic Index” on the web, find a sports club for biking, jogging or walking, concentrate on eating and use small spoons and forget about diets.
There is long-standing discussion, how the body signals by “being hungry” that something is missing (sorry, only 1 historic reference). Of course this works also in non-humans: Have you ever seen supersized animals? My guess is, that the well developed and unconscious food recognition process is largely fooled by pre-processed food that contains additives changing appearance, taste and smelling. So, you have now heard the first time about the fake food hypothesis. I do not believe so much in voluntarily overeating – it seems much more an involuntary repeated intake to find someting useful.
Coming back to our start: Imagine that
drugs that can block hunger (as we now learned the search for required food ingredients) and imagin that the developed world continues to eat their currently preferred food: Everybody will then need a professional nutrionists to balances his/her daily intake. So, we better save tax payer money for these BMI-gene studies. Yea, yea.

Nightmare

An anonymous reader at slashdot writes that AOL released search logs of 657,427 users “AOL has released very private data about its users without their permission. While the AOL username has been changed to a random ID number, the ability to analyze all searches by a single user will often lead people to easily determine who the user is, and what they are up to. The data includes personal names, addresses, social security numbers and everything else someone might type into a search box.” The German Green Party already filed a legislation proposal that companies and institutions will need to inform their clients about such accidents. This seems to be very important also for genetic data. Yea, yea.