Axel Skytthe

Environmental and Heritable Factors in the Causation of Cancer — Analyses of Cohorts of Twins from Sweden, Denmark, and Finland

BACKGROUND The contribution of hereditary factors to the causation of sporadic cancer is unclear. Studies of twins make it possible to estimate the overall contribution of inherited genes to the development of malignant diseases. METHODS We combined data on 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. Statistical modeling was used to estimate the relative importance of heritable and environmental factors in causing cancer at 11 of those sites. RESULTS At least one cancer occurred in 10,803 persons among 9512 pairs of twins. An increased risk was found among the twins of affected persons for stomach, colorectal, lung, breast, and prostate cancer. Statistically significant effects of heritable factors were observed for prostate cancer (42 percent; 95 percent confidence interval, 29 to 50 percent), colorectal cancer (35 percent; 95 percent confidence interval, 10 to 48 percent), and breast cancer (27 percent; 95 percent confidence interval, 4 to 41 percent). CONCLUSIONS Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. This finding indicates that the environment has the principal role in causing sporadic cancer. The relatively large effect of heritability in cancer at a few sites suggests major gaps in our knowledge of the genetics of cancer.

Heritability of Adult Body Height: A Comparative Study of Twin Cohorts in Eight Countries

A major component of variation in body height is due to genetic differences, but environmental factors have a substantial contributory effect. In this study we aimed to analyse whether the genetic architecture of body height varies between affluent western societies. We analysed twin data from eight countries comprising 30,111 complete twin pairs by using the univariate genetic model of the Mx statistical package. Body height and zygosity were self-reported in seven populations and measured directly in one population. We found that there was substantial variation in mean body height between countries; body height was least in Italy (177 cm in men and 163 cm in women) and greatest in the Netherlands (184 cm and 171 cm, respectively). In men there was no corresponding variation in heritability of body height, heritability estimates ranging from 0.87 to 0.93 in populations under an additive genes/unique environment (AE) model. Among women the heritability estimates were generally lower than among men with greater variation between countries, ranging from 0.68 to 0.84 when an additive genes/shared environment/unique environment (ACE) model was used. In four populations where an AE model fit equally well or better, heritability ranged from 0.89 to 0.93. This difference between the sexes was mainly due to the effect of the shared environmental component of variance, which appears to be more important among women than among men in our study populations. Our results indicate that, in general, there are only minor differences in the genetic architecture of height between affluent Caucasian populations, especially among men.

Age- and Sex-differences in the Validity of Questionnaire-based Zygosity in Twins.

Questionnaire-based zygosity assessment in twins has generally been found to be valid. In this report we evaluate sex- and age-differences in the validity of such questionnaire-based classification when using the four questions that have been the basis of zygosity assessment in The Danish Twin Registry for half a century. Three hundred and forty-two male and 531 female twin pairs were zygosity diagnosed using genetic markers and the results compared with the original questionnaire based classification. We found significant differences in the accuracy of questionnaire based zygosity diagnosis when stratifying the data for sex as well as age: males and monozygotic having the highest misclassification. However, even in the group with the highest misclassification rate the frequency was less than 8%. The overall misclassification rate was only 4%, with a clear tendency towards a higher proportion of misclassified monozygotic than dizygotic twins. The results demonstrate that questionnaire based zygosity diagnosis can still be regarded as a valid and valuable classification method for most purposes.

The Danish Twin Registry: 127 birth cohorts of twins.

The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.

Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study

Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome‐wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12‐q22 (LOD = 2.95), chromosome 19p13.3‐p13.11 (LOD = 3.76), and chromosome 19q13.11‐q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed‐effect meta‐analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P‐value = 9.6 × 10−8). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11‐q13.32 with P‐value = 0.02 and P‐value = 1.0 × 10−5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12‐q22, and 19p13.3‐p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

Familial Risk and Heritability of Cancer Among Twins in Nordic Countries

IMPORTANCE Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction. OBJECTIVE To estimate familial risk and heritability of cancer types in a large twin cohort. DESIGN, SETTING, AND PARTICIPANTS Prospective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (N = 203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up. EXPOSURES Shared environmental and heritable risk factors among pairs of twins. MAIN OUTCOMES AND MEASURES The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twins development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death. RESULTS A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%). CONCLUSIONS AND RELEVANCE In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.

Concordance for multiple sclerosis in Danish twins: an update of a nationwide study

The occurrence of multiple sclerosis (MS) in twins has not previously been studied in complete nationwide data sets. The existence of almost complete MS and twin registries in Denmark ensures that essentially unbiased samples of MS cases among twins can be obtained. In this population-based study, virtually all Danish MS cases among twins born before 1983 with onset of MS after 1948 and diagnosis before 1 January 1997 were identified. Of 13 286 MS cases, 178 were twins and, of these 164 twin pairs were discordant and seven were concordant. We found significantly higher proband-wise concordance among monozygotic twins than dizygotic twins, with estimated proband-wise concordances of 24% (95% confidence interval (CI): 5-39%) for monozygotic and 3% (95% CI: 0-8%) for dizygotic twins. Thus, a monozygotic twin whose co-twin has MS has a 24% risk of developing the disease, while the corresponding risk for a dizygotic twin is only 3%. Our results largely confirm previously published concordance estimates and indicate that genetic factors are of importance in susceptibility to MS.

A cohort study of recurrence patterns among more than 54,000 relatives of oral cleft cases in Denmark: support for the multifactorial threshold model of inheritance

Objectives To determine if the anatomical severity of oral clefting affects familial recurrence in a large population based sample. To provide reliable recurrence risk estimates for oral cleft for first, second, and third degree relatives. Design Population based cohort study. Setting Denmark. Participants 6776 individuals affected with an oral cleft born from 1952 to 2005 and 54 229 relatives. Main outcome measures Recurrence risk estimates for oral cleft for first, second, and third degree relatives and stratification by severity, specificity, parent of origin effect, and family size for first degree relatives. Results For cleft lip and palate probands we observed recurrence risks for first, second, and third degree relatives of respectively 3.5% (95% CI 3.1% to 4.0%), 0.8% (95% CI 0.6% to 1.0%), and 0.6% (95% CI 0.4% to 0.8%). Individuals affected by the most severe oral cleft had a significantly higher recurrence risk among both offspring and siblings, eg, the recurrence risk for siblings of a proband with isolated bilateral cleft lip with cleft palate was 4.6% (95% CI 3.2 to 6.1) versus 2.5% (95% CI 1.8 to 3.2) for a proband born with a unilateral defect. Conclusions Anatomical severity does have an effect on recurrence in first degree relatives and the type of cleft is predictive of the recurrence type. Highly reliable estimates of recurrence have been provided for first cousins in addition to more accurate estimates for first and second degree relatives. These results and the majority of prior data continue to support a multifactorial threshold model of inheritance.

The causal direction in the association between respiratory syncytial virus hospitalization and asthma.

BACKGROUND Earlier studies have reported an increased risk of asthma after respiratory syncytial virus (RSV) hospitalization. Other studies found that asthmatic disposition and propensity to wheeze increase the risk of RSV hospitalization. OBJECTIVE The current study examined the causal direction of the associations between RSV hospitalization and asthma in a population-based cohort of twins. METHODS We conducted a prospective cohort study examining the associations between RSV hospitalization and asthma by using registry information on RSV hospitalization and asthma among 18,614 Danish twins born 1994 to 2003. The associations between RSV and asthma were examined in both directions: we examined the risk of asthma after RSV hospitalization, and the risk of RSV hospitalization in children with asthma in the same population-based cohort. RESULTS Asthma hospitalization after RSV hospitalization was increased as much as 6-fold to 8-fold during the first 2 months after RSV hospitalization but was no longer increased 1 year later. Asthma increased the risk of RSV hospitalization by 3-fold, and the risk was not time-dependent. Analyzing these associations on the basis of asthma defined from use of inhaled corticosteroid did not materially change the risk estimates. CONCLUSION There is a bidirectional association between severe RSV infection and asthma. Severe RSV infection is associated with a short-term increase in the risk of subsequent asthma, suggesting that RSV induce bronchial hyperresponsiveness; and asthma is associated with a long-term increased susceptibility for severe RSV disease, suggesting a host factor being responsible for the severe response to RSV infection. This suggests that severe RSV infection and asthma may share a common genetic predisposition and/or environmental exposure.

Longevity studies in genomEUtwin

Previous twin studies have indicated that approximately 25% of the variation in life span can be attributed to genetic factors and recent studies have also suggested a moderate clustering of extreme longevity within families. Here we discuss various definitions of extreme longevity and some analytical approaches with special attention to the challenges due to censored data. Lexis diagrams are provided for the Danish, Dutch, Finnish, Italian, Norwegian, and Swedish Twin registries hereby outlining possibilities for longevity studies within GenomEUtwin. We extend previous analyses of lifespan for the Danish 1870-1900 twin cohorts to include the new 1901-1910 cohorts, which are consistent with the previous findings. The size of the twin cohorts in GenomEUtwin and the existence of population-based, nationwide health and death registers make epidemiological studies of longevity very powerful. The combined GenomEUtwin sample will also allow detailed age-specific heritability analyses of lifespan. Finally, it will provide a resource for identifying unusual sibships (i.e., dizygotic twin pairs) where both survived to extreme ages, as a basis for discovering genetic variants of importance for extreme survival.