View Full Version : Another search for endophenotypes.

11-25-15, 11:50 AM
Not conclusive, of course, but interesting.

Linkage and association analysis of ADHD endophenotypes in extended and multigenerational pedigrees from a genetic isolate (

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.

11-25-15, 02:26 PM
Interesting, but what are endophenotypes?

Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.

Okay, now how are they tested for?

11-25-15, 06:06 PM
Okay, now how are they tested for?
The key is in the first sentence of what you quoted -- they must be measurable in some way.

How the measurement/assessment is actually done will depend on the particular endophenotype under consideration.

Some examples of things that might be considered "endophenotypes" -- and measured -- might be, say, scores below a cutoff on a test of working memory, brain activation patterns in an fMRI study, scores above a cutoff on the "planning" portion of an executive function rating scale, certain ratios of sizes of brain parts based on imaging, etc.

Each of these may be associated with particular genotypes (possibly in concert with other factors).

With ADHD, it is likely there will be numerous valid endophenotypes found, not all of which will fit the whole group of people currently diagnosed with ADHD -- based on different distinct and shared causal pathways. The idea is that identifying these more "basic"/"biological" and consistently measurable characteristics or patterns will lead to better understanding of the connections between the diagnosis of ADHD, how the symptoms actually arise, and the underlying genetic influences.

11-26-15, 04:43 AM
I think Namazu made the point before that all of these silly complex genetic disorder studies end up with statistically significant clinically insignificant findings.
Awful lot of effort for little in return.

It's a bit like a starving man spending all of his money in a posh restaurant on a tiny modern cuisine plate of truffles just because he happens to be living in a hole outside its door.
Far better to go for a walk and find a 5 for 1 greengrocer deal on low glycaemic index fermentable veggies to feed his gut bacteria and keep him alive for life instead of just a couple of tortured minutes.

What is it with truffles anyway ?
(^^ this comment has nothing to do with truffles)

One wonders whether science is a little like an attention deficit :-) child searching (self-medication) for the next big thing (toy!!) to numb the pain of existence.