#head circumference

A paper published in the journal Endocrinology reports an interesting Mendelian Randomisation (MR) study on the causal association of thyroid hormones—TSH, T4—on blood lipid profiles. A specific aspect of this study grasped my interest. The authors studied the causal association of thyroid hormones on blood lipid profiles within the physiological range. What is special about studying a causal association within the physiological range, you might wonder.

Whenever I cross paths with an MR paper, my first thought will be: is it possible to answer the same question using the conventional approach, a randomized controlled trial (RCT)? Often, the scenario will be that it’s not possible, and this makes the study interesting as it gives me an opportunity to appreciate the fact that human genetics is enabling scientists to find answers for biological questions that otherwise cannot be found. And that’s why I often hand pick such studies and tweet to my followers. This study is one such example.

The authors of this study wanted to answer the question: do  TSH and T4, within the physiological range, causally influence blood lipid levels? It is not possible to conduct an RCT for this. Because, one, it is not ethical to intentionally administer thyroid hormone to an otherwise healthy person, and two, it is not easy—perhaps, not possible—to trivially increase or decrease the TSH or T4 levels in the blood without bouncing them off the physiological range because even slight changes in their levels will provoke the hormonal feedback systems.

The MR analysis indeed showed that an increase in TSH level, within the physiological range, causally leads to increases in the LDL and total cholesterol levels in the blood. Similarly, a decrease in T4 level, within the physiological range, causally leads to increases in the LDL and total cholesterol levels in the blood. It’s amazing that we can find these effects by leveraging human genetics, isn’t it?

Another reason--in fact, the main reason—why I found this study interesting is it kickstarted a train of thought in me about human cognition.

Although I work mainly on the genetics of brain-related phenotypes, being trained as a medical doctor, it’s in my nature to be interested in the genetics of all human diseases and traits.  Often, I find that learning about the genetics of traits and diseases whose biological mechanisms are simple and straightforward helps to improve my understanding of the genetics of brain-related diseases and traits. Or at least, it helps me to appreciate their complexities on a deeper level. When I read this paper, I couldn’t resist comparing the relationship between thyroid hormones and lipids with the relationship between head circumference and cognition (intelligence, if you like). And the differences are indeed fascinating.

The positive relationship between thyroid hormones, T4, for example, and cholesterol levels is observed throughout the distribution spectrum, and not just within the physiological range. Extremely low levels of T4 (i.e. clinical hypothyroidism) lead to hypercholesterolemia and similarly, extremely high levels of T4 (i.e. clinical hyperthyroidism) lead to hypocholesterolemia. On the other hand, if you consider the head circumference and cognition, within the physiological range (i.e. within plus or minus 2 SDs of the population average) there exists a positive relationship between the two (many will frown upon this, however, the association has been robustly demonstrated using MR using strong genetic instruments). However, outside the physiological range, extremely low (microcephaly) and extremely high head circumference (macrocephaly,) both lead to extremely poor cognition (i.e. intellectual disability). This is due to a phenomenon called haploinsufficiency.

Hold tight, now I am dragging you through a rabbit hole through which I was dragged through by my train of thought.

Most of the brain-specific genes are haploinsufficient or dosage-sensitive, that is, either decreased (e.g. loss of one allele) or increased dosages (e.g. duplication of the gene) of these genes lead to loss of function. This dosage sensitivity can be well appreciated if we look at the effect of copy number variations (CNVs) on cognition, where both deletions, as well as duplications, lead to poor cognition (see these threads mine: thread1, thread2). This is, however, not the case for head circumference. There are many examples of CNVs where deletion leads to microcephaly and duplication leads to macrocephaly, and the phenomenon is called the mirroring effect. I’ve written twitter threads on this (thread1, thread2). Note that the dosage sensitivity works only on the brain function (cognition), but not on the brain structure (head circumference or brain volume). When we take a slightly deeper look, we will realize that the molecular functions of the dosage-sensitive genes themselves are not affected. The gene is, of course, transcribed to mRNA, the mRNA, to protein, which indeed performs its molecular function, e.g. brain cells proliferation in the case of head circumference. But the final phenotype, the higher-level function (i.e. cognition) is what is sensitive to the gene dosage. So, a foolproof system is in place, beyond the boundaries of the central dogma, to protect the brain from going awry. This is, of course, a design that evolution has perfected over millions and millions of years.

This foolproof system is why there exist no rare variants that boost cognition. Even a recent rare variants association analysis in almost 500,000 individuals in the UK Biobank didn’t yield any large effect positive association for intelligence. It is, of course, unrealistic to expect a large effect negative association in UKBB as the participants here are cognitively healthy.

Likewise, this foolproof system is why there exists no evidence of positive selection of genetic variants for cognition or any brain-related phenotypes, for that matter, in any of the human populations. And we will not find any in the future either. This means it’s theoretically impossible to find biological differences in cognition between human populations, at least due to evolutionary adaptation. Because no random rare mutations can ever increase cognition beyond a threshold as all brain-specific genes are dosage sensitive. They can only do so below the threshold, which will be outside the natural selection’s radar. And that explains why common variants additively have such a huge effect on human cognition. All those tiny sneaky bastards who have escaped natural selection and managed to survive in the population.

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Abstract

Head circumference inter-orbital index is an important parameter in craniofacial anthropometry. The knowledge of its normal values for a particular region can be used in the treatment of certain craniofacial abnormalities. This study was conducted in Otolo, Okofia, Nnewi, Anambra State, Nigeria. A total of 349 (175females and 174males) adult…

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