Mono- and biallelic variant effects on disease at biobank scale.

Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics1. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance2,3. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.

Standard clinical computed tomography fails to precisely visualise presence, course and branching points of deep cerebral perforators.

BACKGROUND: Standard computed tomography (CT) images have earned a well-established position in neuroimaging. Despite that, CT is somehow limited by its resolution, which does not enable to distinctively visualise structures smaller than 300 µm in diameter. Perforating arteries, most of which measure 100-400 µm in diameter, supply important subcortical structures (thalamus, basal ganglia, internal capsule). Consequently, pathologies affecting these vessels (e.g. lacunar strokes) can have a devastating clinical outcome. The aim of our study was to assess standard CT's ability to visualise perforators and compare it with microscopic and micro-CT pictures. MATERIALS AND METHODS: We have obtained 6 brainstem and 17 basal ganglia specimens. We infused them with barium sulphate contrast medium administered into either vertebral or internal cerebral artery. After that, the specimens were fixed in formalin and subsequently a series of CT, micro-CT and microscopic examinations were performed. RESULTS: The median number of visualised perforators in brainstem and basal ganglia specimens was 8 and 3, respectively for CT and 18 and 7 for micro-CT (p < 0.05). Standard CT failed to clearly visualise branching points and vessels smaller than 0.25-0.5 mm (1-2 voxels) in diameter. Parallel vessels, like lenticulostriate arteries could not be differentiated in standard CT due to their proximity being smaller that the resolution. CONCLUSIONS: Basing on our results, we infer that CT is a poor modality for imaging of the perforators, presenting both quantitative and qualitative flaws in contrast with micro-CT.