High Risk Population Isolate Reveals Low Frequency Variants Predisposing to Intracranial Aneurysms

Abstract

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42×10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.

Selling vs. non-selling neuro-oncology research cohorts and manuscripts in the eyes of a grumpy reviewer after 2,000 reviews

“…A d v a n c e d s t a t i s t i c a l m e t h o d s a n d c l i n i c a l bioinformaticians Non-parametric statistics are preferable (e.g., median vs. mean; Mann-Whitney U-test vs. Student's T-test) because most clinical cohorts do not present normal variations anyway. It seems that the young generation has adopted, e.g., Kaplan-Meier analysis and Cox models for the handling of incomplete follow-up data and time-dependent end variables (see 7). We would suggest a few more methods to impress the reviewers and support potential readers, such as meta-analysis of previous relevant cohorts [8]; multiple imputation for missing data [1,10] at least to show that the authors were alert; competing risks analysis [4].…”

“…The biggest blunder in presenting a neurooncology cohort is not to have the past histological samples re-classified by neuropathologist(s)-the WHO classification is evolving continuously, and past diagnostics and subtypings are heterogeneous, even erroneous. It does not matter if there are ten authors, once the cohort and data are solid and up to date, and presented accordingly-genomic articles may contain tens or hundreds of authors [7,13].…”

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…[35] A recent study revealed four novel low-frequency risk loci utilizing an alternative genetic approach. [36] The study focused on the Finnish population, enriched the percentage of familial IA patients in the discovery sample, and increased genome-wide coverage through imputing genotyped variants against the 1000 genomes project reference panel (v3, March 2012 release). [36] The first novel variant rs74972714 at 2q23.3 is located 40 Kb downstream of LYPD6.…”

“…[36] The study focused on the Finnish population, enriched the percentage of familial IA patients in the discovery sample, and increased genome-wide coverage through imputing genotyped variants against the 1000 genomes project reference panel (v3, March 2012 release). [36] The first novel variant rs74972714 at 2q23.3 is located 40 Kb downstream of LYPD6. [36] LYPD6 can inhibit transcriptional activity of the AP-1 transcription factor complex, a key activated mediator of inflammation in endothelial cells subject to atherogenic blood flow conditions.…”

“…[36] The first novel variant rs74972714 at 2q23.3 is located 40 Kb downstream of LYPD6. [36] LYPD6 can inhibit transcriptional activity of the AP-1 transcription factor complex, a key activated mediator of inflammation in endothelial cells subject to atherogenic blood flow conditions. [37,38] The variant rs113816216 at 5q31.3 is located in the intron of FSTL4, a poorly characterized gene.…”