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JAMA May 2014Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental...
IMPORTANCE
Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved.
OBJECTIVE
To provide estimates of familial aggregation and heritability of ASD.
DESIGN, SETTING, AND PARTICIPANTS
A population-based cohort including 2,049,973 Swedish children born 1982 through 2006. We identified 37,570 twin pairs, 2,642,064 full sibling pairs, 432,281 maternal and 445,531 paternal half sibling pairs, and 5,799,875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained.
MAIN OUTCOMES AND MEASURES
The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors.
RESULTS
In the sample, 14,516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100,000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64).
CONCLUSIONS AND RELEVANCE
Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.
Topics: Adolescent; Adult; Autistic Disorder; Child; Child, Preschool; Cohort Studies; Female; Genetic Predisposition to Disease; Humans; Male; Maternal Age; Paternal Age; Registries; Risk; Sweden; Twins, Monozygotic; Young Adult
PubMed: 24794370
DOI: 10.1001/jama.2014.4144 -
JAMA Jun 2018Psychiatric reactions to life stressors are common in the general population and may result in immune dysfunction. Whether such reactions contribute to the risk of...
IMPORTANCE
Psychiatric reactions to life stressors are common in the general population and may result in immune dysfunction. Whether such reactions contribute to the risk of autoimmune disease remains unclear.
OBJECTIVE
To determine whether there is an association between stress-related disorders and subsequent autoimmune disease.
DESIGN, SETTING, AND PARTICIPANTS
Population- and sibling-matched retrospective cohort study conducted in Sweden from January 1, 1981, to December 31, 2013. The cohort included 106 464 exposed patients with stress-related disorders, with 1 064 640 matched unexposed persons and 126 652 full siblings of these patients.
EXPOSURES
Diagnosis of stress-related disorders, ie, posttraumatic stress disorder, acute stress reaction, adjustment disorder, and other stress reactions.
MAIN OUTCOMES AND MEASURES
Stress-related disorder and autoimmune diseases were identified through the National Patient Register. The Cox model was used to estimate hazard ratios (HRs) with 95% CIs of 41 autoimmune diseases beyond 1 year after the diagnosis of stress-related disorders, controlling for multiple risk factors.
RESULTS
The median age at diagnosis of stress-related disorders was 41 years (interquartile range, 33-50 years) and 40% of the exposed patients were male. During a mean follow-up of 10 years, the incidence rate of autoimmune diseases was 9.1, 6.0, and 6.5 per 1000 person-years among the exposed, matched unexposed, and sibling cohorts, respectively (absolute rate difference, 3.12 [95% CI, 2.99-3.25] and 2.49 [95% CI, 2.23-2.76] per 1000 person-years compared with the population- and sibling-based reference groups, respectively). Compared with the unexposed population, patients with stress-related disorders were at increased risk of autoimmune disease (HR, 1.36 [95% CI, 1.33-1.40]). The HRs for patients with posttraumatic stress disorder were 1.46 (95% CI, 1.32-1.61) for any and 2.29 (95% CI, 1.72-3.04) for multiple (≥3) autoimmune diseases. These associations were consistent in the sibling-based comparison. Relative risk elevations were more pronounced among younger patients (HR, 1.48 [95% CI, 1.42-1.55]; 1.41 [95% CI, 1.33-1.48]; 1.31 [95% CI, 1.24-1.37]; and 1.23 [95% CI, 1.17-1.30] for age at ≤33, 34-41, 42-50, and ≥51 years, respectively; P for interaction < .001). Persistent use of selective serotonin reuptake inhibitors during the first year of posttraumatic stress disorder diagnosis was associated with attenuated relative risk of autoimmune disease (HR, 3.64 [95% CI, 2.00-6.62]; 2.65 [95% CI, 1.57-4.45]; and 1.82 [95% CI, 1.09-3.02] for duration ≤179, 180-319, and ≥320 days, respectively; P for trend = .03).
CONCLUSIONS AND RELEVANCE
In this Swedish cohort, exposure to a stress-related disorder was significantly associated with increased risk of subsequent autoimmune disease, compared with matched unexposed individuals and with full siblings. Further studies are needed to better understand the underlying mechanisms.
Topics: Adult; Autoimmune Diseases; Female; Follow-Up Studies; Humans; Male; Middle Aged; Proportional Hazards Models; Registries; Retrospective Studies; Risk Factors; Selective Serotonin Reuptake Inhibitors; Siblings; Socioeconomic Factors; Stress Disorders, Post-Traumatic; Stress Disorders, Traumatic; Stress, Psychological; Sweden
PubMed: 29922828
DOI: 10.1001/jama.2018.7028 -
Translational Psychiatry Feb 2023Individuals with autism spectrum disorder (ASD), in addition to the core features of the disease, experience a higher burden of co-occurring medical conditions. This...
Individuals with autism spectrum disorder (ASD), in addition to the core features of the disease, experience a higher burden of co-occurring medical conditions. This study sought to describe the frequency and distribution of comorbidit conditions in individuals with ASD, and systematically evaluate the possibility that pre- and postnatal exposures (e.g., preterm birth, hypoxia at birth, traumatic brain injury, and fetal alcohol syndrome) associated with ASD may also be linked with distinct comorbidities. We used the SPARK study database, launched by the Simons Foundation Autism Research Initiative (SFARI). Comorbidities considered in the study included neurological, cognitive, psychiatric, and physical conditions. The study sample consisted of 42,569 individuals with ASD and their 11,389 non-ASD siblings (full and half siblings). Majority (74%) of individuals with ASD had at least one comorbidity, and had a greater average number of comorbidities than their non-ASD siblings. Preterm birth and hypoxia at birth were the most common peri-natal exposures in the sample. In logistic regression models adjusted for covariates, these exposures were associated with several distinct comorbidities in ASD cases, including attention and behavior problems, psychiatric and neurological disorders, and growth conditions. A similar pattern of association was also observed in non-ASD siblings. Our findings underscore that individuals with ASD experience a greater burden of comorbidities, which could be partly attributable to the higher rates of perinatal exposures compared to their non-ASD siblings. Study findings, if replicated in other samples, can inform the etiology of comorbidity in ASD.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Autism Spectrum Disorder; Premature Birth; Comorbidity; Autistic Disorder; Siblings
PubMed: 36841830
DOI: 10.1038/s41398-023-02374-w -
Fa Yi Xue Za Zhi Apr 2019Objective To evaluate the effectiveness of single nucleotide polymorphism (SNP) genoty-ping in combination with identity by state (IBS) strategy in full sibling...
Objective To evaluate the effectiveness of single nucleotide polymorphism (SNP) genoty-ping in combination with identity by state (IBS) strategy in full sibling testing. Methods Thirty-five blood samples were collected from a four-generation family. Ninety autosomal SNPs were genotyped using Precision ID Identity Panel. The distribution of IBS scores for full siblings and other relationships were calculated and compared. The relationships were determined using Fisher discriminant function and threshold method, respectively. Results Based on family members and previous research, 44, 30, 111, 71 and 1 000 pairs of full siblings (FS), grandparent-grandchild (GG), uncle/aunt-nephew/niece (UN), first cousins (FC) and unrelated individuals (UI) were obtained, respectively. The average IBS scores were 148, 130, 132, 124 and 120, respectively. Except for the GG and UN pairs, the distribution differences among the other relationships had statistical significance (<0.05). The false rates of Fisher discriminant function to determine relationships were 1.3%, 22.3%, 17.0% and 38.7% for FS, GG, UN and FC, respectively. Based on the simulation data, the thresholds =128 and =141 were recommended to determine full sibling relationships (the false rate ≤0.05%). Conclusion The 90 SNP genetic markers included in the Precision ID Identity Panel meet the testing requirements for full sibling relationships. The threshold method based on IBS has a relatively lower false rate and is more flexible.
Topics: Genotype; Genotyping Techniques; Humans; Polymorphism, Single Nucleotide; Siblings
PubMed: 31135116
DOI: 10.12116/j.issn.1004-5619.2019.02.014 -
BMC Medicine Sep 2023Full-cohort and sibling-comparison designs have yielded inconsistent results about the impacts of caesarean delivery on offspring health outcomes, with the effect... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Full-cohort and sibling-comparison designs have yielded inconsistent results about the impacts of caesarean delivery on offspring health outcomes, with the effect estimates from the latter being more likely directed towards the null value. We hypothesized that the seemingly conservative results obtained from the sibling-comparison design might be attributed to inadequate adjustment for non-shared confounders between siblings, particularly maternal age at delivery.
METHODS
A systematic review and meta-analysis was first conducted. PubMed, Embase, and the Web of Science were searched from database inception to April 6, 2022. Included studies (1) examined the association of caesarean delivery, whether elective or emergency, with offspring health outcomes; (2) simultaneously conducted full-cohort and sibling-comparison analyses; and (3) reported adjusted effect estimates with 95% confidence intervals (95% CIs). No language restrictions were applied. Data were extracted by 2 reviewers independently. Three-level meta-analytic models were used to calculate the pooled odds ratios (ORs) and 95% CIs for caesarean versus vaginal delivery on multiple offspring health outcomes separately for full-cohort and sibling-comparison designs. Subgroup analyses were performed based on the method of adjustment for maternal age at delivery. A simulation study was then conducted. The simulated datasets were generated with some key parameters derived from the meta-analysis.
RESULTS
Eighteen studies involving 21,854,828 individuals were included. The outcomes assessed included mental and behavioral disorders; endocrine, nutritional and metabolic diseases; asthma; cardiorespiratory fitness; and multiple sclerosis. The overall pooled OR for estimates from the full-cohort design was 1.14 (95% CI: 1.11 to 1.17), higher than that for estimates from the sibling-comparison design (OR = 1.08; 95% CI: 1.02 to 1.14). Stratified analyses showed that estimates from the sibling-comparison design varied considerably across studies using different methods to adjust for maternal age at delivery in multivariate analyses, while those from the full-cohort design were rather stable: in studies that did not adjust maternal age at delivery, the pooled OR of full-cohort vs. sibling-comparison design was 1.10 (95% CI: 0.99 to 1.22) vs. 1.06 (95% CI: 0.85 to 1.31), in studies adjusting it as a categorical variable, 1.15 (95% CI: 1.11 to 1.19) vs. 1.07 (95% CI: 1.00 to 1.15), and in studies adjusting it as a continuous variable, 1.12 (95% CI: 1.05 to 1.19) vs. 1.12 (95% CI: 0.98 to 1.29). The severe underestimation bias related to the inadequate adjustment of maternal age at delivery in sibling-comparison analyses was fully replicated in the simulation study.
CONCLUSIONS
Sibling-comparison analyses may underestimate the association of caesarean delivery with multiple offspring health outcomes due to inadequate adjustment of non-shared confounders, such as maternal age at delivery. Thus, we should be cautious when interpreting the seemingly conservative results of sibling-comparison analyses in delivery-related studies.
Topics: Female; Pregnancy; Humans; Siblings; Cesarean Section; Delivery, Obstetric; Asthma; Outcome Assessment, Health Care
PubMed: 37679672
DOI: 10.1186/s12916-023-03030-2 -
Genetics, Selection, Evolution : GSE Apr 2023The construction of covariance matrices that account for the genetic relationships among individuals, using pedigree or genotype data, is integral to genetic...
The construction of covariance matrices that account for the genetic relationships among individuals, using pedigree or genotype data, is integral to genetic evaluations, which are now routinely used in the field of animal breeding. The objective of the present study was to estimate the standard deviation in the proportion of the segregating genome that is shared between pairs of full-sibling cattle and sheep independently. Post edits, genotype data comprising 46,069 autosomal single nucleotide polymorphisms (SNPs) were available for 4532 unique full-sibling sheep pairs, as well as for their respective parents. Post edits, genotypes from 50,493 autosomal SNPs were also available for 10,000 unique full-sibling cattle pairs, as well as their respective parents. Genomic relationship matrices were constructed for the sheep and cattle populations, separately. After accounting for both parental genomic inbreeding and the genomic relationship between both parents, the standard deviation in full-sibling cattle and sheep genomic relationships was 0.040 and 0.037 units, respectively. In addition, the intercept value from a linear regression model which regressed each full-sibling genomic relationship on both sire and dam inbreeding, as well as the genomic relationship between the parents, was 0.499 (0.001) for sheep and 0.500 (0.001) for cattle, conforming to the expectation that full-siblings, on average, share 50% of their segregating genome.
Topics: Cattle; Animals; Sheep; Humans; Siblings; Genome; Genotype; Inbreeding; Genomics; Pedigree; Polymorphism, Single Nucleotide
PubMed: 37072693
DOI: 10.1186/s12711-023-00802-5 -
Circulation. Genomic and Precision... Apr 2023Complete atrioventricular block (CAVB) is a major reason for implantation of permanent pacemakers, but knowledge of CAVB inheritance is sparse. This nationwide study...
BACKGROUND
Complete atrioventricular block (CAVB) is a major reason for implantation of permanent pacemakers, but knowledge of CAVB inheritance is sparse. This nationwide study aimed to determine the occurrence of CAVB in first-, second-, and third-degree relatives (full siblings, half-siblings, and cousins).
METHODS
The Swedish multigeneration register was linked to the Swedish nationwide patient register for the period 1997 to 2012. All Swedish full sibling, half-sibling, and cousin pairs born to Swedish parents between 1932 and 2012 were included. Competing risks and time-to-event, subdistributional hazard ratios (SHRs) according to Fine and Gray and hazard ratios using Cox proportional hazards model were estimated using robust SEs and considering the relatedness of relatives (full siblings, half-siblings, cousins). Additionally, odds ratios (ORs) for CAVB were calculated for traditional cardiovascular comorbidities.
RESULTS
The study population (N=6 113 761) consisted of 5 382 928 full siblings, 1 266 391 half-siblings, and 3 750 913 cousins. In total, 6442 (0.11%) unique individuals were diagnosed with CAVB. Of these, 4200 (65.2%) were males. SHRs for CAVB were 2.91 for full siblings (95% CI, 2.43-3.49), 1.51 for half-siblings (0.56-4.10), and 3.54 for cousins (1.73-7.26) of affected individuals. Age-stratified analysis showed higher risk in young individuals born from 1947 to 1986: SHR, 5.30 (3.78-7.43) for full siblings, SHR, 3.30 (1.06-10.31) for half-siblings, and SHR, 3.15 (1.39-7.17) for cousins. Similar familial HRs according to Cox proportional hazard model and ORs were obtained without any major differences. Apart from familial relationship, CAVB was associated with hypertension (OR, 1.83), diabetes (OR, 1.41), coronary heart disease (OR, 2.08), heart failure (OR, 5.01), and structural heart disease (OR, 4.59).
CONCLUSIONS
Risk of CAVB among relatives of affected individuals depends on relationship degree, being strongest in young siblings. The familial association extending to third-degree relatives indicates presence of genetic components in the cause of CAVB.
Topics: Male; Humans; Female; Sweden; Atrioventricular Block; Family; Siblings; Parents
PubMed: 36802810
DOI: 10.1161/CIRCGEN.121.003654 -
Bipolar Disorders Jun 2023To investigate associations of neonatal characteristics and pregnancy complications with bipolar disorder (BPD) in offspring.
OBJECTIVES
To investigate associations of neonatal characteristics and pregnancy complications with bipolar disorder (BPD) in offspring.
METHODS
We conducted a nationwide cohort study among 2,059,578 non-malformed singleton live-births in Sweden born 1983-2004. Using national registries with prospectively recorded information, we followed participants for a BPD diagnosis from 13 up to 34 years of age. We compared BPD risks between exposure categories using hazard ratios (HR) with 95% confidence intervals (CI) from adjusted Cox models. We also conducted sibling-controlled analyses among 1,467,819 full siblings.
RESULTS
There were 14,998 BPD diagnoses. Risk of BPD was 0.74% through 25 years of age. Very/extremely preterm birth (22 to 31 weeks) was related to increased BPD HRs in sibling-controlled analyses; compared with a gestational age of 37 weeks, adjusted HR (95% CI) for 31, 28, and 22 weeks were, respectively, 1.31 (0.99, 1.74), 2.09 (1.15, 3.79), and 5.74 (1.15, 28.63). Spontaneous but not medically indicated very/extremely preterm birth was associated with increased risk. Compared with vaginal birth, caesarean section birth was associated with 1.20 (1.08, 1.33) and 1.58 (1.06, 2.36) times higher BPD risk in general and sibling cohorts, respectively. Small-for-gestational age (SGA) birth was related to increased BPD HRs in general cohort and sibling analyses (HRs [95% CI] were 1.22 [1.06, 1.39] and 1.68 [1.13, 2.50], respectively); only term SGA was associated with increased risk. Head circumference-for-gestational age, gestational diabetes, preeclampsia, and placental abruption were not associated with BPD.
CONCLUSIONS
Very/extremely preterm birth, caesarean birth, and SGA are related to BPD incidence.
Topics: Infant, Newborn; Humans; Pregnancy; Female; Infant; Siblings; Cohort Studies; Cesarean Section; Bipolar Disorder; Premature Birth; Placenta; Fetal Growth Retardation; Pregnancy Complications
PubMed: 37081589
DOI: 10.1111/bdi.13327 -
BMJ (Clinical Research Ed.) Jan 2023To investigate the association between gestational age at birth and cognitive outcomes in adolescence.
OBJECTIVE
To investigate the association between gestational age at birth and cognitive outcomes in adolescence.
DESIGN
Nationwide population based full sibling cohort study.
SETTING
Denmark.
PARTICIPANTS
1.2 million children born between 1 January 1986 and 31 December 2003, of whom 792 724 had one or more full siblings born in the same period.
MAIN OUTCOME MEASURES
Scores in written language (Danish) and mathematics examinations as graded by masked assessors at the end of compulsory schooling (ninth grade, ages 15-16 years), in addition to intelligence test score at military conscription (predominantly at age 18 years) for a nested sub-cohort of male adolescents. School grades were standardised as z scores according to year of examination, and intelligence test scores were standardised as z scores according to year of birth.
RESULTS
Among 792 724 full siblings in the cohort, 44 322 (5.6%) were born before 37+0 weeks of gestation. After adjusting for multiple confounders (sex, birth weight, malformations, parental age at birth, parental educational level, and number of older siblings) and shared family factors between siblings, only children born at <34 gestational weeks showed reduced mean grades in written language (z score difference -0.10 (95% confidence interval -0.20 to -0.01) for ≤27 gestational weeks) and mathematics (-0.05 (-0.08 to -0.01) for 32-33 gestational weeks, -0.13 (-0.17 to -0.09) for 28-31 gestational weeks, and -0.23 (-0.32 to -0.15) for ≤27 gestational weeks), compared with children born at 40 gestational weeks. In a nested sub-cohort of full brothers with intelligence test scores, those born at 32-33, 28-31, and ≤27 gestational weeks showed a reduction in IQ points of 2.4 (95% confidence interval 1.1 to 3.6), 3.8 (2.3 to 5.3), and 4.2 (0.8 to 7.5), respectively, whereas children born at 34-39 gestational weeks showed a reduction in intelligence of <1 IQ point, compared with children born at 40 gestational weeks.
CONCLUSIONS
Cognitive outcomes in adolescence did not differ between those born at 34-39 gestational weeks and those born at 40 gestational weeks, whereas those with a gestational age of <34 weeks showed substantial deficits in multiple cognitive domains.
Topics: Child; Infant, Newborn; Pregnancy; Female; Humans; Male; Adolescent; Infant; Gestational Age; Siblings; Cohort Studies; Parturition; Cognition
PubMed: 36653028
DOI: 10.1136/bmj-2022-072779 -
MedRxiv : the Preprint Server For... Mar 2024Postpartum psychosis, a mood disorder triggered by childbirth, is one of the most severe psychiatric conditions, with high risks of suicide and infanticide if untreated....
OBJECTIVE
Postpartum psychosis, a mood disorder triggered by childbirth, is one of the most severe psychiatric conditions, with high risks of suicide and infanticide if untreated. While it is evident that genetic factors play a crucial role in disorder risk, the exact extent of their importance is yet to be determined.
METHODS
This cohort study consisted of 1,648,759 women from the Swedish nationwide registers, of whom 2,514 (0.15%) experienced postpartum psychosis within three months of their first-ever childbirth. We estimated the relative recurrence risk of postpartum psychosis for female full siblings and cousins as a measure of familial, genetic, and environmental risk.
RESULTS
Relative recurrence risk of postpartum psychosis in full siblings was 10.69 (95% CI=6.60-16.26) when adjusted for year of and age at childbirth. Although cousins showed an elevated relative recurrence risk, these results did not reach statistical significance (1.78, 95% CI=0.70-3.62). Despite the higher familial risk of postpartum psychosis among full siblings, the absolute risk for women with an affected sibling is relatively low, estimated at 1.55% within the entire population.
CONCLUSIONS
The observed increased risk of postpartum psychosis in full siblings suggests both genetic and shared environmental influences. However, the lack of significant results in cousins hampers a definitive distinction between these factors. Furthermore, despite increased relative recurrence risk in siblings, their overall likelihood of developing postpartum psychosis remains low. Our study underscores the need for further research to better understand the intricate interplay of genetics and environment in the development of postpartum psychosis.
PubMed: 37546727
DOI: 10.1101/2023.07.20.23292910