Ástrós Skúladóttir

Analysis of sequence diversity in the human genome is fundamental for genetic studies. Structural variants (SVs) are frequently omitted in sequence analysis studies, although each has a relatively large impact on the genome. Here, we present GraphTyper2, which uses pangenome graphs to genotype SVs and small variants using short-reads. Comparison to the syndip benchmark dataset shows that our SV genotyping is sensitive and variant segregation in families demonstrates the accuracy of our approach. We demonstrate that incorporating public assembly data into our pipeline greatly improves sensitivity, particularly for large insertions. We validate 6,812 SVs on average per genome using long-read data of 41 Icelanders. We show that GraphTyper2 can simultaneously genotype tens of thousands of whole-genomes by characterizing 60 million small variants and half a million SVs in 49,962 Icelanders, including 80 thousand SVs with high-confidence.

Abstract Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (OR IDD = 0.92, P = 1.6 × 10 −39 ; OR dorsalgia = 0.92, P = 7.2 × 10 −15 ) is with a 3’UTR variant (rs1871452-T) in CHST3 , encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1 , encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10 −11 ); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

= 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.