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Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

STUDY QUESTION: Are genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)? SUMMARY ANSWER: A wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI. WHAT IS KNOWN ALREADY: POI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7–15% of POI cases. STUDY DESIGN, SIZE, DURATION: This population-based study included 5011 women diagnosed with POI in 1988–2017. The data were collected from various national registries and covers women with POI nationwide. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date. MAIN RESULTS AND THE ROLE OF CHANCE: Of the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1–1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1–39.1). For autosomal single gene disorders, the OR was 16

Purpose: This case–control study assesses the independent roles of reproductive history, postmenopausal hormonal therapy (HT), socioeconomic status (SES), and occupational physical activity on the risk of breast cancer (BC). Methods: Odds ratios (OR) were estimated from conditional logistic multivariate regression model in a data set of 19,253 Finnish women diagnosed with BC between 1994 and 2013 and 96,265 age-matched population controls. Results: Both pre- and postmenopausal white-collar workers had significantly increased risk of ductal and lobular BC as compared to manual workers. Moderate occupational physical activity reduced risk of lobular BC by 14%. There was a transient increase in the risk of BC observed after each birth followed by a protective effect starting some years after the delivery. As the number of children increased, the short-term excess risk was lower and protective effect was observed earlier. Continuous estrogen-progestin therapy (EPT) significantly increased the risk of both ductal and lobular BC and the magnitude of risk was directly proportional to duration of use (OR for 5+ years of use 2.26, 95% confidence interval 2.12–2.42). Monthly EPT for 5+ years increased the risk (OR 1.32, 95% CI 1.20–1.45). Users of estradiol plus levonorgestrel intrauterine system devices showed ORs of 1.56 (95% CI 1.45–1.69) and 2.18 (95% CI 1.81–2.64) for ductal and lobular BC, respectively. Conclusions: This study concludes that pregnancy has a dual effect on BC risk, with a transient increase in risk followed by a long-term protective effect. The SES and HT have a large effect on BC risk while occupational physical activity has only a small independent effect.

STUDY QUESTION: What is the incidence of premature ovarian insufficiency (POI), has the incidence of POI changed over time, and what is the risk of POI among relatives of POI women? SUMMARY ANSWER: The incidence of POI increased among females aged 15–19 years from 2007 onwards and decreased in older age groups, and among relatives of women with POI the risk of POI is significantly increased. WHAT IS KNOWN ALREADY: So far, there has been no good quality, nationwide studies of the incidence of POI. Early menopause has been associated with the elevated risk of early menopause among relatives, but the knowledge of the familial risk of POI is scarce. Lower socioeconomic status has been associated with lower age at natural menopause. STUDY DESIGN, SIZE, DURATION: Population-based study with 5011 women diagnosed with POI in 1988–2017. The data were collected from national registries and covers POI subjects in entire Finland. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with hormone replacement therapy reimbursement for POI were identified from Social Insurance Institution (SII). We calculated POI incidence in different age groups and studied the changes in the incidence rate over time in 5-year segments. Four population-based controls were selected from the Digital and Population Data Services Agency (DVV) for each POI woman. Family members of the POI cases and controls were identified from the DVV and linked to SII reimbursement data to identify POI diagnoses among them. The familial risk of POI was estimated with a logistical regression model. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence was highest in the 35–39 age group, ranging from 73.8/100 000 women-years in 1993–1997 to 39.9/100 000 women-years in 2013–2017. From 2007, the incidence among 15- to 19-year-olds rose from 7.0 to 10.0/100 000 women-years in 2015–2017. Cumulative incidence of POI for women under 40 years in 1988–2017 was 478/100 000 women. The relative risk of POI among relatives of wom

Background: The aim was to examine the hypothesis that antireflux surgery with fundoplication improves long-term survival compared with antireflux medication in patients with reflux oesophagitis or Barrett's oesophagus. Method: Individuals aged between 18 and 70 years with reflux oesophagitis or Barrett's oesophagus (intestinal metaplasia) documented from in-hospital and specialized outpatient care were selected from national patient registries in Denmark, Finland, Iceland, and Sweden from 1980 to 2014. The study investigated all-cause mortality and disease-specific mortality, comparing patients who had undergone open or laparoscopic antireflux surgery with fundoplication versus those using antireflux medication. Multivariable Cox regression analysis was used to estimate hazard ratios (HRs) with 95 per cent confidence intervals for all-cause mortality and disease-specific mortality, adjusted for sex, age, calendar period, country, and co-morbidity. Results: Some 240 226 patients with reflux oesophagitis or Barrett's oesophagus were included, of whom 33 904 (14.1 per cent) underwent antireflux surgery. The risk of all-cause mortality was lower after antireflux surgery than with use of medication (HR 0.61, 95 per cent c.i. 0.58 to 0.63), and lower after laparoscopic (HR 0.56, 0.52 to 0.60) than open (HR 0.80, 0.70 to 0.91) surgery. After antireflux surgery, mortality was decreased from cardiovascular disease (HR 0.58, 0.55 to 0.61), respiratory disease (HR 0.62, 0.57 to 0.66), laryngeal or pharyngeal cancer (HR 0.35, 0.19 to 0.65), and lung cancer (HR 0.67, 0.58 to 0.80), but not from oesophageal cancer (HR 1.05, 0.87 to 1.28), compared with medication, The decreased mortality rates generally remained over time. Cconclusion: In patients with reflux oesophagitis or Barrett's oesophagus, antireflux surgery is associated with lower mortality from all causes, cardiovascular disease, respiratory disease, laryngeal or pharyngeal cancer, and lung cancer, but not from oesopha

Background & Aims: Absolute rates and risk factors of short-term outcomes after antireflux surgery remain largely unknown. We aimed to clarify absolute risks and risk factors for poor 90-day outcomes of primary laparoscopic and secondary antireflux surgery. Methods: This population-based cohort study included patients who had primary laparoscopic or secondary antireflux surgery in the 5 Nordic countries in 2000–2018. In addition to absolute rates, we analyzed age, sex, comorbidity, hospital volume, and calendar period in relation to all-cause 90-day mortality (main outcome), 90-day reoperation, and prolonged hospital stay (≥2 days over median stay). Multivariable logistic regression provided odds ratios (ORs) with 95% confidence intervals (95% CI), adjusted for confounders. Results: Among 26,193 patients who underwent primary laparoscopic antireflux surgery, postoperative 90-day mortality and 90-day reoperation rates were 0.13% (n = 35) and 3.0% (n = 750), respectively. The corresponding rates after secondary antireflux surgery (n = 1 618) were 0.19% (n = 3) and 6.2% (n = 94). Higher age (56–80 years vs 18–42 years: OR, 2.66; 95% CI 1.03-6.85) and comorbidity (Charlson Comorbidity Index ≥2 vs 0: OR, 6.25; 95% CI 2.42-16.14) increased risk of 90-day mortality after primary surgery, and higher hospital volume suggested a decreased risk (highest vs lowest tertile: OR, 0.58; 95% CI, 0.22-1.57). Comorbidity increased the risk of 90-day reoperation. Higher age and comorbidity increased risk of prolonged hospital stay after both primary and secondary surgery. Higher annual hospital volume decreased the risk of prolonged hospital stay after primary surgery (highest vs lowest tertile: OR, 0.74; 95% CI, 0.67-0.80). Conclusion: These findings suggest that laparoscopic antireflux surgery has an overall favorable safety profile in the treatment of gastroesophageal reflux disease, particularly in younger patients without severe comorbidity who undergo surgery at high

Y Background: The aim was to examine the hypothesis that antireflux surgery with fundoplication improves long-term survival compared with antireflux medication in patients with reflux oesophagitis or Barrett's oesophagus.Method: Individuals aged between 18 and 70 years with reflux oesophagitis or Barrett's oesophagus (intestinal metaplasia) documented from in-hospital and specialized outpatient care were selected from national patient registries in Denmark, Finland, Iceland, and Sweden from 1980 to 2014. The study investigated all-cause mortality and disease-specific mortality, comparing patients who had undergone open or laparoscopic antireflux surgery with fundoplication versus those using antireflux medication. Multivariable Cox regression analysis was used to estimate hazard ratios (HRs) with 95 per cent confidence intervals for all-cause mortality and disease-specific mortality, adjusted for sex, age, calendar period, country, and co-morbidity.Results: Some 240 226 patients with reflux oesophagitis or Barrett's oesophagus were included, of whom 33 904 (14.1 per cent) underwent antireflux surgery. The risk of all-cause mortality was lower after antireflux surgery than with use of medication (HR 0.61, 95 per cent c.i. 0.58 to 0.63), and lower after laparoscopic (HR 0.56, 0.52 to 0.60) than open (HR 0.80, 0.70 to 0.91) surgery. After antireflux surgery, mortality was decreased from cardiovascular disease (HR 0.58, 0.55 to 0.61), respiratory disease (HR 0.62, 0.57 to 0.66), laryngeal or pharyngeal cancer (HR 0.35, 0.19 to 0.65), and lung cancer (HR 0.67, 0.58 to 0.80), but not from oesophageal cancer (HR 1.05, 0.87 to 1.28), compared with medication, The decreased mortality rates generally remained over time.Conclusion: In patients with reflux oesophagitis or Barrett's oesophagus, antireflux surgery is associated with lower mortality from all causes, cardiovascular disease, respiratory disease, laryngeal or pharyngeal cancer, and lung cancer

Background: Bariatric surgery carries a risk of severe postoperative complications, sometimes leading to reinterventions or even death. The incidence and risk factors for reintervention and death within 90 days after bariatric surgery are unclear, and were examined in this study. Methods: This population‐based cohort study included all patients who underwent bariatric surgery in one of the five Nordic countries between 1980 and 2012. Data on surgical and endoscopic procedures, diagnoses and mortality were retrieved from national high‐quality and complete registries. Multivariable Cox regression analysis was used to calculate hazard ratios (HRs), adjusted for country, age, sex, co‐morbidity, type of surgery and approach, year and hospital volume of bariatric surgery. Results: Of 49 977 patients, 1111 (2·2 per cent) had a reintervention and 95 (0·2 per cent) died within 90 days of bariatric surgery. Risk factors for the composite outcome reintervention/mortality were older age (HR 1·65, 95 per cent c.i. 1·36 to 2·01, for age at least 50 years versus less than 30 years) and co‐morbidity (HR 2·66, 1·53 to 4·62, for Charlson co‐morbidity index score 2 or more versus 0). The risk of reintervention/mortality was decreased for vertical banded gastroplasty compared with gastric bypass (HR 0·37, 0·28 to 0·48) and more recent surgery (HR 0·51, 0·39 to 0·67, for procedures undertaken in 2010 or later versus before 2000). Sex, surgical approach (laparoscopic versus open) and hospital volume did not influence risk of reintervention/mortality, but laparoscopic surgery was associated with a lower risk of 90‐day mortality (HR 0·29, 0·16 to 0·53). Conclusion: Reintervention and death were uncommon events within 90 days of bariatric surgery even in this unselected nationwide cohort from five countries. Older patients with co‐morbidities have an increased relative risk of these outcomes.

Background: The length of interval between successive childbirths (birth interval) might influence the incidence of breast cancer, either by stimulating or by inhibiting the factors that are responsible for the initiation of breast cancer or its early development. Methods: This is a case-control study nested in a cohort of 47,479 Finnish grand-multiparous (GM) women born after 1934, and registered as having had at least five births before 2013. The 1354 women with breast cancer diagnosis were compared with controls (1:5) matched by parity and date of birth of the mother. Conditional logistic regression was used to estimate odds ratios of the risk of ductal and lobular breast cancer subtypes associated with each of the intervals between the 1st and 5th birth, stratified by age at diagnosis. Age at first and last birth before index date were used as covariates. Results: Increased intervals between the 1st and 5th births were associated with an increased risk of lobular breast cancer. In contrast, regarding ductal cancer, premenopausal women with shorter length of interval (< 2 years) between the 1st and 2nd birth had greater risk and longer intervals (3+ years) were associated with reduced risk. Spacing between the 2nd and 5th birth did not influence the risk of ductal breast cancer. Conclusion: The findings of our study suggest that the effect of the length of birth interval on breast cancer depends on the age and histology. The protective effect of shorter birth intervals on lobular breast among postmenopausal women and the opposite effect on ductal cancer in premenopausal women may reflect distinct differentiation and functional roles of lobular and ductal cells, and possibly also different response to hormonal exposure.

Background & Aims: Bariatric surgery might reduce overall mortality from obesity. We investigated whether the survival times of patients who have had bariatric surgery are similar to those of the general population and are longer than of obese individuals who did not receive surgery. Methods: We performed a population-based cohort study of persons with a diagnosis of obesity listed in nationwide registries from Nordic countries from 1980 through 2012. Bariatric surgery was analyzed in relation to all-cause mortality and the obesity-related morbidities cardiovascular disease, diabetes, cancer, and suicide. Poisson models provided standardized mortality ratios (SMRs) with 95% confidence intervals (CIs). Multivariable Cox regression provided hazard ratios (HRs) for mortality in participants who did and did not have surgery. Results: Among 505,258 participants, 49,977 had bariatric surgery. Overall all-cause SMR was increased after surgery (1.94; 95% CI, 1.83–2.05) and increased with longer follow-up, to 2.28 (95% CI, 2.07–2.51) at ≥15 years after surgery. SMRs were increased for cardiovascular disease (2.39; 95% CI, 2.17–2.63), diabetes (3.67; 95% CI, 2.85–4.72), and suicide (2.39; 95% CI, 1.96–2.92) but not for cancer (1.05; 95% CI, 0.95–1.17); SMRs increased with time. In obese participants who did not have surgery, all-cause SMR was 2.15 (95% CI, 2.11–2.20), which remained stable during follow-up. Compared with obese participants who did not have surgery, patients who had bariatric surgery had decreased overall mortality from all causes (HR, 0.63; 95% CI, 0.60–0.66), cardiovascular disease (HR, 0.57; 95% CI, 0.52–0.63), and diabetes (HR, 0.38; 95% CI, 0.29–0.49) but increased mortality from suicide (HR, 1.68; 95% CI, 1.32–2.14). Cancer mortality was decreased overall (HR, 0.84; 95% CI, 0.76–0.93) but increased at ≥15 years of follow-up (HR, 1.20; 95% CI, 1.02–1.42). Conclusions: In a study of persons with a diagnosis of obesity listed in nationwide regi