Wiring the Brain

The case of the ‘ missing heritability ’ has become celebrated, by some, as a supposed indicator of just how abjectly the Human Genome Project has failed to live up to its promise. We’ve known for a long time that many human traits and common disorders are quite heritable. The HGP was supposed to reveal the underlying genetic causes, paving the way for deeper understanding and new therapies. But genetics seemed to keep coming up short, finding some causal variants but leaving most of the heritability unexplained, or ‘missing’. A new study (along with a lot of supporting theory and other empirical evidence) shows that the answer lies in genetic variants that are much rarer in the population than those that had typically been studied.   (https://pixabay.com/photos/puzzle-dna-research-genetic-piece-2500333/)   It is common knowledge that many human traits run in families, as does risk of common disorders like heart disease, asthma, or mental i...

There was much excitement in the press and in the psychiatric research community recently as a flurry of papers was published, presenting the work of the PsychENCODE project. This project, involving the work of many labs, aimed to deploy the powerful tools of genomics to dissect the landscape of gene regulation in the human brain, with the ultimate goal of revealing the molecular underpinnings of psychiatric disease. Genome-wide association studies ( GWAS ) have revealed hundreds of common genetic variants that are statistically associated with increased risk of psychiatric disorders, such as schizophrenia, ADHD, bipolar disorder, and, to a lesser extent, autism. What they have not revealed is how such variants increase risk of disease. The PsychENCODE project aimed to generate a set of data that would allow researchers to answer that question. There are a number of challenges in going from identification of an associated risk variant to elucid...

--> A paper published today represents a true landmark in psychiatric genetics. It reports results of a genome-wide association study (GWAS) of schizophrenia, involving 36,989 cases and 113,075 controls. Assembling this sample required collaboration on a massive scale, with over 300 authors involved. This huge sample gives unprecedented statistical power to detect genetic variants that predispose to disease, even if their individual effects on risk are tiny. The study reports 108 regions of the genome where genetic differences affect risk of disease. This achievement is rightly being widely celebrated and reported, but what do these results really mean? GWAS look at sites in the genome where the particular base in the DNA sequence is variable – it might sometimes be an “A”, other times a “T”, for example. There are millions of such sites in the human genome (which comprises over 3 billion bases of sequence). Each such site represents a mutation that happened some ...

--> “ Whereof one cannot speak, thereof one must be silent ” - Wittgenstein That’s a maxim to live by, or certainly to blog by, but I am about to break it. Most of the time I try to write about things I feel I have some understanding of (rightly or wrongly) or at least an informed opinion on. But I am writing this post from a position of ignorance and confusion. I want to discuss a fairly esoteric and technical statistical method recently applied in human genetics, which has become quite influential. The results from recent studies using this approach have a direct bearing on an important question – the genetic architecture of complex diseases, such as schizophrenia and autism. And that, in turn, dramatically affects how we conceptualise these disorders. But this discussion will also touch on a much wider social issue in science, which is how highly specialised statistical claims are accepted (or not) by biologists or clinicians, the vast majority of whom are unabl...