Professor Aarno Palotie, M.D., Ph.D. is the research director of the Human Genomics program at FIMM. He is also a faculty member at the Center for Human Genome Research at the Massachusetts General Hospital in Boston and associate member of the Broad Institute of MIT and Harvard. He has a long track record in human disease genetics. He has held professorships and group leader positions at the University of Helsinki, UCLA, and the Wellcome Trust Sanger Institute. He has also been the director of the Finnish Genome Center and Laboratory of Molecular Genetics in the Helsinki University Hospital.FinnGen is now producing very interesting results in polygenic risk prediction and clinical / public health applications of genomics. Below are a few recent papers.
1. This paper studies the use of PRS in prediction of five common diseases, with an eye towards clinical utility.
Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers
Nature Medicine volume 26, 549–557(2020)
Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1,2,3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.
2. This paper is a well-powered study of genetic influence on alcohol use and effects on mortality.
Nature Translational Psychiatry volume 10, Article number: 23 (2020)
While polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85–12.58 g, p = 2.3 × 10–58). The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 (95% CI = 1.66–2.01, p = 1.6 × 10–36). When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI = 1.26–1.99, p = 8.2 × 10–5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI = 1.20–1.47, p = 4.5 × 10–8) in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.
3. This paper examines rare CNVs (Copy Number Variants) and PRS (Polygenic Risk Score) prediction using a combined Finnish sample of ~30k for whom education, income, and health outcomes are known. The study finds that low polygenic scores for Educational Attainment (EA) and intelligence predict worse outcomes in education, income, and health.
Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variantsFrom the paper:https://www.nature.com/articles/s41380-021-01026-zAbstract Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.
... we compared the impact of CNVs to the impact of the PRSs for educational attainment , schizophrenia , and general intelligence  on general health, morbidity, mortality, and socioeconomic burden. We analyzed these effects in two cohorts: one sampled at random from the Finnish working-age population (FINRISK), the other a Finnish birth cohort (Northern Finland Birth Cohort 1966; NFBC1966). Both cohorts link to national health records, enabling analysis of longitudinal health data and socioeconomic status data over several decades.
... we observed a clear polygenic effect on socioeconomic outcome with educational attainment and IQ PRS scores. Belonging to the matched lowest PRS extremes (lowest 2.66%) of educational attainment or IQ had an overall stronger impact on the socioeconomic outcome than belonging to most high-risk CNV groups, and a generally stronger impact on health and survival, with the exception of household income-associated CNVs.
... odds for subsequent level of education were even lower at the matched lowest extreme of PRSEA (OR = 0.31 [0.26–0.37]) and PRSIQ (OR = 0.51 [0.44–0.60]).
... Rare deleterious variants, including CNVs, can have a major impact on health outcomes for an individual and are thus under strong negative selection. However, such variants might not always have a strong phenotypic impact (incomplete penetrance), and as observed here, can have a very modest—if any—effect on well-being. The reason for this wide spectrum of outcomes remains speculative. From a genetic perspective, one hypothesis is that additional variants, both rare and common, modify the phenotypic outcome of a CNV carrier (Supplementary Figs. 11 and 12). This type of effect is observable in analyzes of hereditary breast and ovarian cancer in the UK Biobank  and in FinnGen , where strong-impacting variants’ penetrance is modified by compensatory polygenic effects.
... As stated above, the observed effect of polygenic scores was broader than that of structural variants. We observed strong effects in PRSs for intelligence and educational attainment on education, income and socioeconomic status.