A genome-wide scan of cleft lip triads identifies parent-of-origin interaction effects between ANK3 and maternal smoking, and between ARHGEF10 and alcohol consumption.

Background: Although both genetic and environmental factors have been reported to influence the risk of isolated cleft lip with or without cleft palate (CL/P), the exact mechanisms behind CL/P are still largely unaccounted for. We recently developed new methods to identify parent-of-origin (PoO) interactions with environmental exposures (PoOxE) and applied them to families with children born with isolated cleft palate only. Here, we used the same genome-wide association study (GWAS) dataset and methodology to screen for PoOxE effects in the larger sample of CL/P triads. Methods: Genotypes from 1594 complete triads and 314 dyads (1908 nuclear families in total) with CL/P were available for the current analyses. Of these families, 1024 were Asian, 825 were European and 59 had other ancestries. After quality control, 341,191 SNPs remained from the original 569,244. The exposures were maternal cigarette smoking, use of alcohol, and use of vitamin supplements in the periconceptional period. The methodology applied in the analyses is implemented in the R-package Haplin. Results: Among Europeans, there was evidence of a PoOxSmoke effect for ANK3 with three SNPs (rs3793861, q=0.20, p=2.6e-6; rs7087489, q=0.20, p=3.1e-6; rs4310561, q=0.67, p=4.0e-5) and a PoOxAlcohol effect for ARHGEF10 with two SNPs (rs2294035, q=0.32, p=2.9e-6; rs4876274, q=0.76, p=1.3e-5). Conclusion: Our results indicate that the detected PoOxE effects have a plausible biological basis, and thus warrant replication in other independent cleft samples. Our demonstration of the feasibility of identifying complex interactions between relevant environmental exposures and PoO effects offers new avenues for future research aimed at unravelling  the complex etiology of cleft lip defects.

Association of Household Income With Life Expectancy and Cause-Specific Mortality in Norway, 2005-2015.

Importance: Examining causes of death and making comparisons across countries may increase understanding of the income-related differences in life expectancy. Objectives: To describe income-related differences in life expectancy and causes of death in Norway and to compare those differences with US estimates. Design and Setting: A registry-based study including all Norwegian residents aged at least 40 years from 2005 to 2015. Exposures: Household income adjusted for household size. Main Outcomes and Measures: Life expectancy at 40 years of age and cause-specific mortality. Results: In total, 3 041 828 persons contributed 25 805 277 person-years and 441 768 deaths during the study period (mean [SD] age, 59.3 years [13.6]; mean [SD] number of household members per person, 2.5 [1.3]). Life expectancy was highest for women with income in the top 1% (86.4 years [95% CI, 85.7-87.1]) which was 8.4 years (95% CI, 7.2-9.6) longer than women with income in the lowest 1%. Men with the lowest 1% income had the lowest life expectancy (70.6 years [95% CI, 69.6-71.6]), which was 13.8 years (95% CI, 12.3-15.2) less than men with the top 1% income. From 2005 to 2015, the differences in life expectancy by income increased, largely attributable to deaths from cardiovascular disease, cancers, chronic obstructive pulmonary disease, and dementia in older age groups and substance use deaths and suicides in younger age groups. Over the same period, life expectancy for women in the highest income quartile increased 3.2 years (95% CI, 2.7-3.7), while life expectancy for women in the lowest income quartile decreased 0.4 years (95% CI, -1.0 to 0.2). For men, life expectancy increased 3.1 years (95% CI, 2.5-3.7) in the highest income quartile and 0.9 years (95% CI, 0.2-1.6) in the lowest income quartile. Differences in life expectancy by income levels in Norway were similar to differences observed in the United States, except that life expectancy was higher in Norway in the lower to middle part of the income distribution in both men and women. Conclusions and Relevance: In Norway, there were substantial and increasing gaps in life expectancy by income level from 2005 to 2015. The largest differences in life expectancy between Norway and United States were for individuals in the lower to middle part of the income distribution.

Body mass index, smoking, and risk of death between 40 and 70 years of age in a Norwegian cohort of 32,727 women and 33,475 men.

Overweight-obesity and smoking are two main preventable causes of premature death. Because the relationship between smoking and body mass index (BMI) complicates the interpretation of associations between BMI and death risks, direct estimates of risks associated with joint exposures are helpful. We have studied the relationships of BMI and smoking to middle age (40-69 years) death risk-overall and by causes-in a Norwegian cohort of 32,727 women and 33,475 men who were 35-49 years old when baseline measurements and lifestyle information were collected in 1974-1988. Individuals with a history of cancer, cardiovascular disease or diabetes at baseline were excluded. Mortality follow-up was through 2009. The relationship between BMI and middle age death risk was U-shaped. Overall middle age death risks were 11% in women and 21 % in men. The combination of obesity and heavy smoking resulted in fivefold increase in middle age death risks in both women and men: For women middle age death risk ranged from 6 % among never smokers in the 22.5-24.9 BMI group to 31% (adjusted 28%) in obese (BMI > 30 kg/m(2)) heavy smokers (≥20 cigarettes/day). The corresponding figures in men were 10% and 53% (adjusted 45%). Obese never smokers and light (1-9 cigarettes/day) smokers in the 22.5-24.9 BMI groups both experienced a twofold increase in middle age risks of death. For women, cancer (56%) was the most common cause of death followed by cardiovascular disease (22%). In men, cardiovascular disease was most common (41%) followed by cancer (34%). Cardiovascular disease deaths were more strongly related to BMI than were cancer deaths.

Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts.

Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures.