Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

Risk of Cardiomyopathy in Younger Persons With a Family History of Death from Cardiomyopathy: A Nationwide Family Study in a Cohort of 3.9 Million Persons.

BACKGROUND: Recommendations for presymptomatic screening of relatives of cardiomyopathy patients are based on findings from tertiary centers. Cardiomyopathy inheritance patterns are fairly well understood, but how cardiomyopathy in younger persons (<50 years) aggregates in families at the population level is unclear. In a nationwide cohort, we examined the risk of cardiomyopathy by family history of premature death (<60 years) from cardiomyopathy. METHODS AND RESULTS: By linking Danish national register data, we constructed a cohort of 3.9 million persons born from 1950 to 2008. We ascertained family history of premature (<60 years) death from cardiomyopathy or other conditions, and cohort members were followed from 1977 to 2008 for cardiomyopathy diagnosed at <50 years. We identified 3890 cardiomyopathies in 89 million person-years of follow-up. Using Poisson regression, we estimated incidence rate ratios for cardiomyopathy by family history of premature death. Premature cardiomyopathy deaths in first- and second-degree relatives were associated with 29- and 6-fold increases in the rate of cardiomyopathy, respectively. If the first-degree relative died aged <35 years, the rate of cardiomyopathy increased 100-fold; given ≥2 premature deaths in first-degree relatives, the rate increased more than 400-fold. In contrast, a family history of premature death from other cardiac or noncardiac conditions increased the rate of cardiomyopathy 3-fold at most. CONCLUSIONS: A family history of premature cardiomyopathy death was associated with an increase in risk of cardiomyopathy ranging from 6- to 400-fold, depending on age, kinship, gender and number of affected family members. Our general population-based results support recommendations for presymptomatic screening of relatives of cardiomyopathy patients.

Determination of NAT2 acetylation status in the Greenlandic population.

N-acetyltransferase 2 (NAT2) is a well-studied phase II xenobiotic metabolizing enzyme relevant in drug metabolism and cancerogenesis. NAT2 activity is largely determined by genetic polymorphisms in the coding region of the corresponding gene. We investigated NAT2 acetylation status in 1556 individuals from Greenland based on four different single nucleotide polymorphism (SNP) panels and the tagging SNP rs1495741. There was good concordance between the NAT2 status inferred by the different SNP combinations. Overall, the fraction of slow acetylators was low with 17.5 % and varied depending on the degree of Inuit ancestry; in individuals with <50 % Inuit ancestry, we observed more than 25 % slow acetylators reflecting European ancestry. Greenland has a high incidence of tuberculosis, and individual dosing of isoniazid according to NAT2 status has been shown to improve treatment and reduce side effects. Our findings could be a first step in pharmacogenetics-based tuberculosis therapy in Greenland.

Epilepsy, anti-epileptic medication use and risk of cancer.

Whether the powerful medications used to treat epilepsy increase the risk of cancer has been debated for decades, but until now no study could disentangle the contributions of anti-epileptic medications and epilepsy itself to cancer risk. Using a cohort comprising all Danish residents ≥ 16 years old at some point during the period 1996-2010 (>56 million person-years of follow-up) and information from national health registers, we examined associations between anti-epileptic medication use and cancer rates in persons with and without epilepsy, and between epilepsy and cancer rates in treated and untreated individuals. Associations were expressed as incidence rate ratios (IRRs) estimated using Poisson regression. Among persons without epilepsy, use of anti-epileptic medication increased the rates of most cancers little or not at all, although we observed moderately increased rates of liver, mouth and throat, and respiratory tract cancers (IRRs 1.40-1.59). In contrast, we observed strong associations between epilepsy and the rates of central nervous system and mouth and throat cancers (IRRs 2.00-3.91), and a modest association between epilepsy and the rate of respiratory tract cancers (IRRs 1.30-1.35), independent of anti-epileptic medication use. Our finding of only modest increases in cancer risk directly attributable to anti-epileptic medication use suggests that these medications may not be as strongly carcinogenic as has been feared, and that it is not primarily anti-epileptic medications that are responsible for the increased cancer risk among epileptics but another aspect of epilepsy diagnosis or treatment or an etiologic factor common to the two conditions.

Continuous Glucose Monitoring-Based Metrics and Hypoglycemia Duration in Insulin-Experienced Individuals With Long-standing Type 2 Diabetes Switched From a Daily Basal Insulin to Once-Weekly Insulin Icodec: Post Hoc Analysis of ONWARDS 2 and ONWARDS 4.

OBJECTIVE: This post hoc analysis assessed continuous glucose monitoring (CGM)-based metrics and hypoglycemia duration with once-weekly insulin icodec versus once-daily basal insulin analogs in insulin-experienced individuals with long-standing type 2 diabetes from two 26-week phase 3a trials (ONWARDS 2 and ONWARDS 4). RESEARCH DESIGN AND METHODS: Time in range (TIR) (3.9-10.0 mmol/L), time above range (TAR) (>10.0 mmol/L), and time below range (TBR) (<3.9 mmol/L and <3.0 mmol/L) were assessed during three CGM time periods (switch [weeks 0-4], end of treatment [weeks 22-26], and follow-up [weeks 27-31]) for icodec versus comparators (ONWARDS 2, insulin degludec [basal regimen]; ONWARDS 4, insulin glargine U100 [basal-bolus regimen]) using double-blind CGM data. CGM-derived hypoglycemic episode duration (<3.9 mmol/L) was assessed. RESULTS: In both trials, there were no statistically significant differences in TIR, TAR, or TBR (<3.0 mmol/L) for icodec versus comparators across all time periods. In the end-of-treatment period, mean TIR was 63.1% (icodec) vs. 59.5% (degludec) in ONWARDS 2 and 66.9% (icodec) vs. 66.4% (glargine U100) in ONWARDS 4. Mean TBR <3.9 mmol/L and <3.0 mmol/L remained within recommended targets (<4% and <1%, respectively) across time periods and treatment arms. Hypoglycemic episode duration (<3.9 mmol/L) was comparable across time periods and treatment arms (median duration ≤40 min). CONCLUSIONS: In insulin-experienced participants with long-standing type 2 diabetes, CGM-based TIR, TAR, and CGM-derived hypoglycemia duration (<3.9 mmol/L) were comparable for icodec and once-daily basal insulin analogs during all time periods. TBR remained within recommended targets.

Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis.

IMPORTANCE: Infantile hypertrophic pyloric stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited. OBJECTIVES: To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets. DESIGN, SETTING, AND PARTICIPANTS: During stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide data set of 1001 Danish surgery-confirmed samples (cases diagnosed 1987-2008) and 2371 disease-free controls. In stage 2, the 5 most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed 1983-2010), Sweden (cases diagnosed 1958-2011), and the United States (cases diagnosed 1998-2005), with a total of 1663 cases and 2315 controls. MAIN OUTCOMES AND MEASURES: Association of genetic variation with the presence of infantile hypertrophic pyloric stenosis. RESULTS: We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio [OR], 1.59; 95% CI, 1.38-1.83; P = 1.9 × 10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS. CONCLUSIONS AND RELEVANCE: This study identified a new genome-wide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation.

Risk of Congenital Heart Defects in Offspring of Affected Mothers and Fathers.

BACKGROUND: Smaller studies have reported a higher offspring risk of congenital heart defects (CHDs) for mothers with CHDs than for fathers with CHDs. In a large population-based study, we investigated whether offspring risk of CHD differed for mothers and fathers with CHDs. METHODS: All people born in Denmark, 1977 to 2011, with at least 1 registered parent, were included in our cohort (n=2 341 061). Parent-child recurrence of CHDs was evaluated using risk ratios (RRs) comparing risks of CHDs in individuals with and without a parent with a CHD, estimated using log-linear binomial regression. RESULTS: The RRs for any CHD in offspring were 5.39 (95% CI, 4.88-5.96) for mothers and 3.04 (95% CI, 2.59-3.57) for fathers affected with any CHD; the ratio of RRs for mothers versus fathers was 1.82 (P<0.0001). Recurrence RRs for the same cardiac phenotype in parent and offspring were significantly stronger for mothers than for fathers for conotruncal defects (ratio of RRs, 4.98), left ventricular outlet tract obstruction (ratio of RRs, 4.98), and ventricular septal defects (ratio of RRs, 2.51) but not for atrioventricular septal defects (ratio of RRs, 1.06). Birth rates among people with CHDs, relative to the general population, were 18% higher for women than for men, regardless of parental cardiac phenotype. CONCLUSIONS: Recurrence risks of CHDs were significantly greater in the offspring of affected women than in the offspring of affected men. The excess maternal recurrence risks could not be explained by the slightly higher birth rates in women with CHDs.

Multivariate Hawkes process models of the occurrence of regulatory elements.

BACKGROUND: A central question in molecular biology is how transcriptional regulatory elements (TREs) act in combination. Recent high-throughput data provide us with the location of multiple regulatory regions for multiple regulators, and thus with the possibility of analyzing the multivariate distribution of the occurrences of these TREs along the genome. RESULTS: We present a model of TRE occurrences known as the Hawkes process. We illustrate the use of this model by analyzing two different publically available data sets. We are able to model, in detail, how the occurrence of one TRE is affected by the occurrences of others, and we can test a range of natural hypotheses about the dependencies among the TRE occurrences. In contrast to earlier efforts, pre-processing steps such as clustering or binning are not needed, and we thus retain information about the dependencies among the TREs that is otherwise lost. For each of the two data sets we provide two results: first, a qualitative description of the dependencies among the occurrences of the TREs, and second, quantitative results on the favored or avoided distances between the different TREs. CONCLUSIONS: The Hawkes process is a novel way of modeling the joint occurrences of multiple TREs along the genome that is capable of providing new insights into dependencies among elements involved in transcriptional regulation. The method is available as an R package from http://www.math.ku.dk/~richard/ppstat/.

Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway.

Background Evidence linking individual-level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996-2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000-2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non-folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80-1.22), 1.08 (95% CI , 0.93-1.25), and 1.07 (95% CI , 0.97-1.19), respectively. For initiation of folic acid in the preconception period weeks -4 to -1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI , 1.00-1.25), 1.09 (95% CI , 0.95-1.25), 0.98 (95% CI , 0.86-1.12), and 0.97 (95% CI , 0.78-1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.

Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.

Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10-10; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Common variants associated with general and MMR vaccine-related febrile seizures.

Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10(-12) versus controls, P = 1.2 × 10(-9) versus MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653: P = 9.6 × 10(-11) versus controls, P = 1.6 × 10(-9) versus MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general, implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 × 10(-16)) and SCN2A (rs3769955: P = 3.1 × 10(-10)), a TMEM16 family gene (ANO3; rs114444506: P = 3.7 × 10(-20)) and a region associated with magnesium levels (12q21.33; rs11105468: P = 3.4 × 10(-11)). Finally, we show the functional relevance of ANO3 (TMEM16C) with electrophysiological experiments in wild-type and knockout rats.

Genome-wide association analyses identify variants in developmental genes associated with hypospadias.

Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P < 5 × 10(-8). Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.

Family history of premature death and risk of early onset cardiovascular disease.

OBJECTIVES: The purpose of this study was to examine the effect of a family history of premature death, cardiovascular death in particular, on the risk of early cardiovascular disease. BACKGROUND: Studies suggest that fatal cardiovascular events and less severe cardiovascular diseases may co-occur in families. Consequently, a family history of premature death may indicate a familial cardiac frailty that predisposes to early cardiovascular disease. METHODS: We ascertained family history of premature death (age <60 years) in all individuals born in Denmark from 1950 to 2008 and followed this cohort for early cardiovascular disease (age <50 years). Using Poisson regression, we estimated incidence rate ratios (IRRs) reflecting the effect of premature death in the family on early cardiovascular disease risk. RESULTS: Among 3,985,301 persons followed up for 89,294,258 person-years, 129,825, 31,172, and 5,214 were diagnosed with any early cardiovascular disease, ischemic heart disease, and ventricular arrhythmia, respectively. IRRs for these conditions given a history of premature cardiovascular death in first-degree relatives were 1.72 (95% confidence interval [CI]: 1.68 to 1.77), 2.21 (95% CI: 2.11 to 2.31), and 1.94 (95% CI: 1.70 to 2.20), respectively. With ≥2 cardiovascular deaths in a family, corresponding IRRs were 3.30 (95% CI: 2.77 to 3.94), 5.00 (95% CI: 3.87 to 6.45), and 6.18 (95% CI: 3.32 to 11.50). The IRR for any early cardiovascular disease given a family history of premature noncardiovascular death was significantly lower, 1.12 (95% CI: 1.10 to 1.14) (p(cardiac vs. noncardiac) < 0.0001). CONCLUSIONS: Family history of premature cardiovascular death was consistently and significantly associated with a risk of early cardiovascular disease, suggesting an inherited cardiac vulnerability. These results should be kept in mind when assessing cardiovascular disease risk in persons with a family history of premature cardiovascular death.

Familial aggregation of lone atrial fibrillation in young persons.

OBJECTIVES: This study investigated whether an individual's risk of developing lone atrial fibrillation (AF) before age 60 years is associated with lone AF in relatives. BACKGROUND: Genetic factors may play a role in the development of lone AF. METHODS: Using Danish national registers, a cohort was established of ~4 million persons born between 1950 and 2008, and those with a family history of lone AF (AF without preceding cardiovascular/endocrine diagnoses) were identified. Individuals were followed up until the first diagnosis of lone AF. Poisson regression was used to estimate incidence rate ratios (IRRs). RESULTS: In ~92 million person-years of follow-up, 9,507 persons were identified as having lone AF. The IRRs for lone AF given an affected first- or second-degree relative were 3.48 (95% confidence interval [CI]: 3.08 to 3.93) and 1.64 (95% CI: 1.04 to 2.59), respectively. IRRs were higher for men than for women but were not associated with the affected relative's sex. IRR for lone AF was 6.24 (95% CI: 2.59 to 15.0), given at least 2 first-degree relatives affected with lone AF. The IRR for lone AF in persons aged <40 years given a first-degree relative affected at age <40 years was 5.42 (95% CI: 3.80 to 7.72), and 8.53 (95% CI: 3.82 to 19.0) in persons age <30 years given a first-degree relative affected at age <30 years. CONCLUSIONS: A family history of lone AF is associated with substantial risk of lone AF, with the strongest risks associated with young age at onset, multiple affected relatives, and in first-degree relatives. These results suggest routine evaluation of the families of at least certain types of patients with lone AF.

Time trends in human fecundability in Sweden.

BACKGROUND: Trends in biologic fertility are elusive. Possible negative trends in male reproductive health are still debated, and their effect on human fertility might be negligible. Time-to-pregnancy (TTP) is a functional measure of couple fecundability. METHODS: We analyzed data on TTP among 832,000 primiparous women 20 years of age and older in the nationwide Swedish Medical Birth Registry from 1983 through 2002. This age restriction led to an exclusion of 10% of primiparous pregnancies. Subfertility (TTP > or =1 year) was analyzed as a function of maternal age, calendar time at initiation of attempt, and birth cohort-taking into account the truncation problems that are inherent in birth-based retrospective sampling. RESULTS: Subfertility generally decreased over successive birth cohorts. When studied as a period effect, a transient increase in subfertility was seen in the early 1990s. Subfertility increased with age, except that for women in their late 1930s, an apparent decrease was observed, particularly among the early cohorts. CONCLUSION: We found decreasing subfertility over time. We speculate that these patterns might be related to a Sweden-specific decrease over time in sexually transmitted diseases, to changes in sexual behavior induced by socioeconomic conditions, or to broader biologic or educational trends.

Feasibility of the current-duration approach to studying human fecundity.

Approaches for monitoring time trends in couples' fecundity and for studying its sensitivity to environmental factors are needed. Two approaches rely on the inclusion of a cross-sectional sample of couples currently "at risk" of pregnancy either with follow up (prevalent cohort) or without follow up (current-duration design). To illustrate the feasibility of the current-duration design, we contacted a random sample of 1204 French women age 18 to 44 years in 2004 and recruited those who were currently having unprotected sexual intercourse. The current duration since the beginning of unprotected intercourse was defined for 69 women (5.7%). An additional 15 women (1.2%) were planning to start trying to become pregnant within the next 6 months. Parametric methods allowed, based on current duration of unprotected intercourse, estimation of fecundity as if the couples had been followed prospectively. The estimated proportion of couples not pregnant after 12 months of unprotected intercourse was 34% (95% confidence interval [CI] = 15-54%). The accelerated-failure time model allows study of the influence of environmental factors on fecundity. As an illustration, tobacco smoking by the woman was associated with a doubling in the median duration of unprotected intercourse before pregnancy (adjusted time ratio = 2.4; 95% CI = 1.1-5.2). We quantified the influence of time trends in the prevalence of smoking on this estimate. We suggest ways to quantify or avoid other potential bias. In conclusion, it is possible to recruit a sample of couples currently having unprotected intercourse. The current-duration design appears feasible with approximately 5 times as many women eligible for study as for an incident cohort design.