… the only thing that is arbitrary about the various orders of a set of terms is our attention, for the terms themselves have always all the orders of which they are capable.Bertrand Russell, Introduction to Mathematical Philosophy
I present here an analysis of the summary statistics elaborated by Neale’s Lab from the raw data released by the UK Biobank, a large-scale biomedical database that includes genetic data on 500,000 UK citizens. I filtered out variants with a minor allele frequency below 0.05, I included only variants that reached a p value below 5⋅10^−7 (even though only p < 5⋅10^−8 was considered for definitive associations), and I filtered out variants with a p value for the Hardy-Weinberg equilibrium below 10^−6.
Females with self-reported Chronic Fatigue Syndrome are associated with a region of chromosome 13 with high linkage disequilibrium, from position 41353297 to 41404706 (on h19) which includes gene SLC25A15. After applying statistical methods of fine-mapping (approximation of the joint model and posterior inclusion probability, PIP), I found rs11147812 (13:41404706:T:C) as the possible causal variant within this region. This same variant is associated with the whole sample of patients (males + females) at 5⋅10^−8 < p < 5⋅10^−7. The relaxed cutoff for statistical significance of 5⋅10^−7 has been recently proposed as a way to increase the rate of true positives without a substantial increase in false positive associations, in studies with a sample of 130,000. Patients presented a reduced frequency of the alternative allele at position 13:41404706, and this is expected to reduce the expression of SLC25A15 in adipose tissue and other tissues. Gene SLC25A15 encodes mitochondrial ornithine transporter I which is involved in the transport of ornithine inside mitochondria.
Males with chronic asthenia not otherwise specified (ICD10: R53) showed an association with a region in high LD of chromosome 18 (18:55452281 to 18:55460845). The only variant from this region with p < 5⋅10^−8 is rs62092652 (18:55454761:G:A) and it is confirmed as the causal variant in this region by PIP calculation. The alternative allele at this position is associated with a reduced expression of gene ATP8B1 in the brain. Since the alternative allele is more frequent in patients than in controls (frequency of 0.3501 and 0.2422, respectively), we may expect to find a reduced expression of ATP8B1 in the brain of patients. ATP8B1 encodes a member of the P-type cation transport ATPase family, which transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to another. These two molecules are both phospholipids found in biological membranes.
Genetic data from the UK Biobank were also used to test previously proposed associations between ME/CFS and variants on TNF: none of the proposed associations was confirmed.
No overlap of the genetic signal from self-reported CFS and R53 was found with the psychiatric traits: bipolar II and depression.
This document also includes an introduction to some of the methods currently employed in the study of GWAS summary statistics.
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