Update on the UK Biobank: analysis on variants with a minor allele frequency between 0.01 and 0.05

Abstract

I report on the association between variants with a minor allele frequency included between 1% and 5% and the phenotypes: self-reported Chronic Fatigue Syndrome and chronic asthenia not otherwise specified (ICD10: R53). The analysis was performed on a metadata file generated from the UK Biobank database. Patients with self-reported CFS (both sexes) showed a significant increase (p = ) in the frequency of the alternative allele of variant rs148723539, 10:131677233:G:A on h19, an SNP of the intronic region of gene EBF3. Female patients with R53 showed a significant association (p = ) with variant rs182581502, 7:56492485:G:T on h19, which belongs to the intronic region of pseudogene RP13-492C18.2 (gene_id: ENSG00000237268.2). This analysis completes a previous one (here) performed only on common variants (minor allele frequency above 5%).

Introduction

In a previous blog post (here), I reported on the association between self-reported Chronic Fatigue Syndrome and a region of chromosome 13, in particular variant rs11147812. This result was obtained by performing a set of analyses on a metadata file generated by Neale’s Lab from the UK Biobank dataset. The analysis included about 14 million variants, 1659 patients (451 males), and 300k controls. I focused on common variants (minor allele frequency above 0.05) and I used a cut-off for statistical significance of . I performed a similar analysis on chronic asthenia not otherwise specified (ICD10: R53) and I found an association between male patients and variant rs62092652.

Here, I report on the results of the same set of analyses for variants with a minor allele frequency below 0.05 and above 0.01. I used a more stringent cut-off for statistical significance of (read this blog post for an introduction to the p value in GWAS).

Methods

I considered again the phenotypes: self-reported CFS and R53. I filtered out variants too far from the Hardy-Weinberg equilibrium (in the total UK Biobank sample) by using a cut-off of when testing the null hypothesis: the alleles are in HWE. I filtered out variants with expected minor allele count below 25, in cases.

Results

When considering self-reported CFS, the only statistically significant association was between variant rs148723539 (10:131677233:G:A on h19) and the group of patients that included both sexes (Table 1). In particular, the association is between the alternative allele and patients (in other words, patients have a higher frequency of the alternative allele A than controls). This is an intronic variant of gene EBF3. No association was found after stratification by sex.

variant	cons	min AF	p val	gene
rs148723539	intron variant	0.0101	2.26e-09	EBF3

When considering chronic asthenia not otherwise specified (ICD10: R53), the analysis for the whole sample (both sexes) gave no associations. When considering females only, variant rs182581502 (7:56492485:G:T on h19) reached statistical significance with the alternative allele more frequent in patients than in controls (Table 2). This is an intronic variant of pseudogene RP13-492C18.2 (gene_id: ENSG00000237268.2). No associations were found for males only.

rsid	cons	min AF	p val	gene
rs182581502	intron variant	0.0286	5.40e-09	RP13-492C18.2

Variant rs182581502 is associated with changes in gene expression of gene CHCHD2 in several tissues (see this page). The alternative allele (the one more frequent in female R53 patients) is associated with an increase in the expression of CHCHD2 in the hippocampus and basal ganglia, for instance. No effects on gene expression have been found for rs148723539.

A concise summary of the results of my analysis of the UK Biobank database is presented in the following table.