Jaakko Arthur Kaprio - Selected Publications#

Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000 Jul 13;343(2):78-85. doi: 10.1056/NEJM200007133430201. PMID: 10891514.

This landmark paper (2777 citations in WoS) estimated the heritability of common cancers identified from combining cancer registry data with twin cohorts from three Nordic countries.

Mucci LA, Hjelmborg JB, Harris JR, Czene K, Havelick DJ, Scheike T, Graff RE, Holst K, Möller S, Unger RH, McIntosh C, Nuttall E, Brandt I, Penney KL, Hartman M, Kraft P, Parmigiani G, Christensen K, Koskenvuo M, Holm NV, Heikkilä K, Pukkala E, Skytthe A, Adami HO, Kaprio J; Nordic Twin Study of Cancer (NorTwinCan) Collaboration. Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA. 2016 Jan 5;315(1):68-76. doi: 10.1001/jama.2015.17703. PMID: 26746459; PMCID: PMC5498110.

Here we extended the follow-up of the NEJM twin cancer paper and included data from Norway (337 citations). The number of cancer sites with significant heritability increased from three to ten, and a number of cancer-site specific papers have been published as well. Two central observations were the importance of genetic factors across the whole age range in adults, and that even among monozygotic (genetically identical) pairs concordant for cancer, the cancer in the two twins were more often at different sites than the same site.

Korhonen T, Hjelmborg J, Harris JR, Clemmensen S, Adami HO, Kaprio J; Nordic Twin Study of Cancer (NorTwinCan) collaboration. Cancer in twin pairs discordant for smoking: The Nordic Twin Study of Cancer. Int J Cancer. 2022 Feb 10. doi: 10.1002/ijc.33963. Epub ahead of print. PMID: 35143046

This new paper from the Nordic Twin Cancer Study provides evidence of a causal role of tobacco smoking in the etiology of tobacco-associated cancers other than lung cancer (for which we have reported results earlier, PMID 29054888, in 2017)

Keskitalo K, Broms U, Heliövaara M, Ripatti S, Surakka I, Perola M, Pitkäniemi J, Peltonen L, Aromaa A, Kaprio J. Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Hum Mol Genet. 2009 Oct 15;18(20):4007-12. doi: 10.1093/hmg/ddp322. Epub 2009 Jul 23. PMID: 19628476; PMCID: PMC2748889.

We were the first to show that the CHRNA5 D398N functional variant accounted for 4% of the variation in cotinine levels among smokers. Very few single variants for any behaviors or complex traits accounted for such a large proportion of variance previously and showed the values of focusing on biomarkers, when available.(89 citations)

Loukola A, Buchwald J, Gupta R, Palviainen T, Hällfors J, Tikkanen E, Korhonen T, Ollikainen M, Sarin AP, Ripatti S, Lehtimäki T, Raitakari O, Salomaa V, Rose RJ, Tyndale RF, Kaprio J. A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism. PLoS Genet. 2015 Sep 25;11(9):e1005498. doi: 10.1371/journal.pgen.1005498. PMID: 26407342; PMCID: PMC4583245.

Nicotine in smokers is metabolized to cotinine and further to 3-OH-cotinine by the enzyme CYP2A6, and the speed to metabolism is associated with quantity smoked and ability to quit smoking. Prior studies on known variants of CYP2A6 gene accounted for c. 4% of the variance. Our study identified multiple common variants in and around CYP2A6 that accounted for over 30% of variance, later extended to about 40% (PMID: 32157176, Buchwald et al, 2021) and opens various pharmacogenetic avenues and personalized treatments for nicotine dependence.(72 citations)

Bollepalli S, Korhonen T, Kaprio J, Anders S, Ollikainen M. EpiSmokEr: a robust classifier to determine smoking status from DNA methylation data. Epigenomics. 2019 Oct;11(13):1469-1486. doi: 10.2217/epi-2019-0206. Epub 2019 Aug 30. PMID: 31466478.

We developed a robust classifier for smoking status using methylation data based on the 450k array. This online tool has been widely adopted for use. (14 citations)

Kujala UM, Kaprio J, Koskenvuo M. Modifiable risk factors as predictors of all-cause mortality: the roles of genetics and childhood environment. Am J Epidemiol. 2002 Dec 1;156(11):985-93. doi: 10.1093/aje/kwf151. PMID: 12446254.

Despite observational studies indicating that physical activity may reduce mortality, the causal nature has not been established. Using twin pairs discordant for behavioral risk factors, we saw associations within pairs consistent with a causal effect on mortality for smoking, but not alcohol use or physical activity. Later work has shown a within-pair association for alcohol as well, but we have not yet seen that physical activity, suggesting that physical activity and mortality may share a common genetic background.(citations 156).

Sillanpää E, Palviainen T, Ripatti S, Kujala UM, Kaprio J. Polygenic Score for Physical Activity Is Associated with Multiple Common Diseases. Med Sci Sports Exerc. 2022 Feb 1;54(2):280-287. doi: 10.1249/MSS.0000000000002788. PMID: 34559723; PMCID: PMC8754097.

Using genome-wide association data on physical activity, we analysed the association of a polygenic risk score (PRS) on morbidity and mortality in FinnGen, and showed that genetic predisposition to physical activity is associated with reduced risk of cardiometabolic disease, but not with dementia. To our knowledge this was the first application of physical activity PRS on risk of disease in a large cohort.

Silventoinen K, Zdravkovic S, Skytthe A, McCarron P, Herskind AM, Koskenvuo M, de Faire U, Pedersen N, Christensen K, Kaprio J; GenomEUtwin Project. Association between height and coronary heart disease mortality: a prospective study of 35,000 twin pairs. Am J Epidemiol. 2006 Apr 1;163(7):615-21. doi: 10.1093/aje/kwj081. Epub 2006 Feb 16. PMID: 16484449.

The GenomEUtwin project was a major EU FP5-funded project in which 8 large twin cohorts harmonized data and published collaborative papers with substantially larger sample sizes than earlier. This European work has been considered in Brussels as an exemplary example of European collaboration in genetics and epidemiology (citations 71). This paper is one of many that resulted.

Silventoinen K, Jelenkovic A, Sund R, Yokoyama Y, Hur YM, Cozen W, Hwang AE, Mack TM, Honda C, Inui F, Iwatani Y, Watanabe M, Tomizawa R, Pietiläinen KH, Rissanen A, Siribaddana SH, Hotopf M, Sumathipala A, Rijsdijk F, Tan Q, Zhang D, Pang Z, Piirtola M, Aaltonen S, Oñncel SY, Aliev F, Rebato E, Hjelmborg JB, Christensen K, Skytthe A, Kyvik KO, Silberg JL, Eaves LJ, Cutler TL, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Song YM, Yang S, Lee K, Franz CE, Kremen WS, Lyons MJ, Busjahn A, Nelson TL, Whitfield KE, Kandler C, Jang KL, Gatz M, Butler DA, Stazi MA, Fagnani C, D'Ippolito C, Duncan GE, Buchwald D, Martin NG, Medland SE, Montgomery GW, Jeong HU, Swan GE, Krasnow R, Magnusson PK, Pedersen NL, Dahl Aslan AK, McAdams TA, Eley TC, Gregory AM, Tynelius P, Baker LA, Tuvblad C, Bayasgalan G, Narandalai D, Spector TD, Mangino M, Lachance G, Burt SA, Klump KL, Harris JR, Brandt I, Nilsen TS, Krueger RF, McGue M, Pahlen S, Corley RP, Huibregtse BM, Bartels M, van Beijsterveldt CE, Willemsen G, Goldberg JH, Rasmussen F, Tarnoki AD, Tarnoki DL, Derom CA, Vlietinck RF, Loos RJ, Hopper JL, Sung J, Maes HH, Turkheimer E, Boomsma DI, Sörensen TI, Kaprio J. Differences in genetic and environmental variation in adult BMI by sex, age, time period, and region: an individual-based pooled analysis of 40 twin cohorts. Am J Clin Nutr. 2017 Aug;106(2):457-466. doi: 10.3945/ajcn.117.153643. Epub 2017 Jul 5. PMID: 28679550; PMCID: PMC5525120.

This paper is one of the flagship papers of the CODAtwins project co-led by Karri Silventoinen and myself (citations 60), which have combined data from almost all twin cohorts globally, with a large European component, to analyse determinants of variation in the genetics of BMI and height.