Researchers at Iceland's deCODE genetics continue to add to the unparalleled body of work that they have put together over the past two decades by combining genomic analyses with Iceland's detailed genealogic and health data.
Over the course of three weeks this autumn, the Icelanders saw three of their papers published online at Nature Genetics. On 29 October, first author Unnur Styrkársdóttir, senior author Kári Stefánsson, and their colleagues added to our knowledge of genetic susceptibility factors for osteoarthritis of the hip and knee, two major contributors to disability during aging.
From the largest meta-analysis to date (17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls from Iceland and the UK), they reported 23 independent associations at 22 loci, 16 of which had not been seen before: 12 for hip and 4 for knee osteoarthritis. The study has added significance because it took care to ensure that the definitions of osteoarthritis were consistent for all the study participants.
A week earlier, Stefánsson's team, led by first author Florian Zink, mined Icelandic data with a more fundamental research goal: to create a new, more detailed map of sites in the genome that are imprinted, i.e., where the allele of one parent is blocked by an epigenetic methyl “cap.” A number of congenital disorders arise from imprinting.
Because Zink and colleagues had access to large datasets of Icelandic genetic data and could identify or impute which methylated nucleotides were inherited, they could rule out other sources of methylation in order to produce a highly detailed map that focuses on imprinted sites. They found 165 new sites, along with 64 that have been reported before.
Among the insights the researchers gleaned from the new map was that the imprinted sites are more numerous along a region of chromosome 15 that gives rise to Prader-Willi and Angelman syndromes than previously thought, with a complex pattern of paternal vs maternally derived imprinting. It also appears that the phenotypes can be less binary--ie.. disease vs no disease--and more continuous along a spectrum.
On November 5, the deCODE group had another Nature Genetics paper published online that showed the versatility of their approaches: This time they set out to shed light on mutations that creep into genomes during the very early stages of fetal development. These de novo mutations (DMNs) are hard to study, and current estimates have been based primarily on modeling.
First author Hákon Jónsson and colleagues explored this question directly in 251 Icelandic families, including quite a few large ones. (13 couples had more than 8 offspring!) This allowed them to compare 1,007 sibling pairs, turning up cases where more than one child had a mutation not found in their parents.
"Depending on the properties of the DNM, the recurrence probability ranges from 0.011% to 28.5%," the authors write. (They have also created an online de novo mutation recurrence calculator for researchers to use)
Jónsson H, Sulem P, Arnadottir GA, Pálsson G, Eggertsson HP, Kristmundsdottir S, Zink F, Kehr B, Hjorleifsson KE, Jensson BÖ, Jonsdottir I, Marelsson SE, Gudjonsson SA, Gylfason A, Jonasdottir A, Jonasdottir A, Stacey SN, Magnusson OT, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Multiple transmissions of de novo mutations in families. Nat Genet. 2018 Dec;50(12):1674-1680.
Styrkarsdottir U, Lund SH, Thorleifsson G, Zink F, Stefansson OA, Sigurdsson JK, Juliusson K, Bjarnadottir K, Sigurbjornsdottir S, Jonsson S, Norland K, Stefansdottir L, Sigurdsson A, Sveinbjornsson G, Oddsson A, Bjornsdottir G, Gudmundsson RL, Halldorsson GH, Rafnar T, Jonsdottir I, Steingrimsson E, Norddahl GL, Masson G, Sulem P, Jonsson H, Ingvarsson T, Gudbjartsson DF, Thorsteinsdottir U, Stefansson K. Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis. Nat Genet. 2018 Dec;50(12):1681-1687.
Zink F, Magnusdottir DN, Magnusson OT, Walker NJ, Morris TJ, Sigurdsson A, Halldorsson GH, Gudjonsson SA, Melsted P, Ingimundardottir H, Kristmundsdottir S, Alexandersson KF, Helgadottir A, Gudmundsson J, Rafnar T, Jonsdottir I, Holm H, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Masson G, Gudbjartsson DF, Thorsteinsdottir U, Halldorsson BV, Stacey SN, Stefansson K. Insights into imprinting from parent-of-origin phased methylomes and transcriptomes. Nat Genet. 2018 Nov;50(11):1542-1552.