This paper could not have come at a worst time for BioMickWatson, who was about to classify us as dinosaurs for asking questions about the fast-rising (and soon to be obsolete) religion of Genome-wide Association Studies (GWAS) to heal complex diseases. Our previous discussions on the topic are linked below -
The new paper, published in American Journal of Human Genetics (thanks @ProfBootyPhD for correction), investigated the validity of associations on a disease/disability that is very relevant for this intellectual debate.
Intellectual disability (ID, formerly called mental retardation) is a developmental brain disorder commonly deﬁned by an IQ below 70 and limitations in both intellectual functioning and adaptive behavior. ID can originate from environmental causes and/or genetic anomalies, and its incidence in children is estimated to be of 1%–2%.
The paper noticed something odd -
One of the ﬁrst genes identiﬁed as involved in XLID is FMR1 (MIM 309550), a target of the unstable expansion mutation responsible for fragile X syndrome (MIM 300624); accounting for about 1%–2% of all ID cases, this mutation still remains the most common cause of XLID.5,6 Since then, the number of genes involved in XLID when mutated has grown exponentially, from only 11 in 1992 to 43 in 2002 and over 100 genes now identiﬁed thank to the efforts of various teams.
What if that exponential rise is due to government pouring increasing amount of money on #GWAS? The paper by Piton et al. suggests that could be the case. They further checked 28 genes #GWASsociated with XLID and brought down the list to 3 ‘likely’ genes and a large number of ‘questionable’ and ‘highly questionable’ ones.
We used this NHLBI cohort to systematically reassess the implication of 106 genes proposed to be involved in monogenic forms of XLID. We particularly question the implication in XLID of ten of them (AGTR2, MAGT1, ZNF674, SRPX2, ATP6AP2, ARHGEF6, NXF5, ZCCHC12, ZNF41, and ZNF81), in which truncating variants or previously published mutations are observed at a relatively high frequency within this cohort. We also highlight 15 other genes (CCDC22, CLIC2, CNKSR2, FRMPD4, HCFC1, IGBP1, KIAA2022, KLF8, MAOA, NAA10, NLGN3, RPL10, SHROOM4, ZDHHC15, and ZNF261) for which replication studies are warranted. We propose that similar reassessment of reported mutations (and genes) with the use of data from large-scale human exome sequencing would be relevant for a wide range of other genetic diseases.
Oh well, it feels like a rerun of Jurassic park movie, when dinosaurs landed in San Diego
We thank the blog of Ken Weiss for bringing this paper to our attention. Readers will enjoy their discussion -
It includes a quote from Aravinda Chakraborty, a leading human geneticist, which starts with -
But while finding and localizing genes isn’t a big challenge any more, it is still very difficult to figure out what they actually do.
Who could have known that in this new era of hypothesis-free and consensus-driven ‘science’?
Readers may note that ecodevoevo blog mentioned another previous study of similar nature -
Another cautionary tale appeared in Cell not long ago. A paper called “Exome Sequencing of Ion Channel Genes Reveals Complex Profiles Confounding Personal Risk Assessment in Epilepsy”, Klassen et al., from Jeffrey Noebels’ lab, reported the results of sequencing the exomes of 237 ion channel genes in people with and without sporadic idiopathic epilepsy. They found that “rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined.” That is, the same ion channel variants assumed to cause epilepsy are found in people without the trait.
BioMickWatson responded to our disagreement in an elegant way -
‘English’ of this Englishman, we presume, refers to his response here, where he found out few trivial spelling errors in Dan Graur’s paper and compared it with incomprehensibility of layman’s abstract of an eQTL paper.