Recent advances in the genetics of preterm birth

Preterm birth is associated with short‐ and long‐term impairments affecting physical, cognitive, and neuropsychiatric health. These sequelae, together with a rising preterm birth rate and increased survival, make prematurity a growing public health issue because of the increased number of individuals with impaired health throughout the life span. Although a major contribution to preterm birth comes from environmental factors, it is also modestly heritable. Little is known about the architecture of this genetic contribution. Studies of common and of rare genetic variation have had limited power, but recent findings implicate variation in both the maternal and fetal genome. There is some evidence risk alleles in mothers may be enriched for processes related to immunity and inflammation, and in the preterm infant, processes related to brain development. Overall genomic discoveries for preterm birth lag behind progress for many other multifactorial diseases and traits. Investigations focusing on gene–environment interactions may also provide insights, but these studies still have a number of limitations. Adequately sized genetic studies of preterm birth are a priority for the future especially given the breadth of its negative health impacts across the life span and the current interest in newborn genome sequencing

Pilot study to establish a prospective neonatal cohort: Study of Preterm Infants and Neurodevelopmental Genes (SPRING).

BACKGROUND: Genetic risk variants and preterm birth are early and potent risk factors for later neuropsychiatric disorders. To understand the interrelationships between these factors, a large-scale genetic study of very preterm (VPT, <32 weeks gestation) infants with prospective follow-up is required. In this paper, we describe a streamlined study approach, using efficient processes for biological and clinical data collection, to feasibly establish such a cohort. METHODS: We sought to recruit 500 VPT families within a 1 year period from neonatal units. Treating clinical teams recruited eligible participants, obtained parent consent, collected blood samples and posted specimens to the research laboratory. We extracted all clinical data from the National Neonatal Research Database, an existing UK resource that captures daily patient-level data on all VPT infants. RESULTS: Between May 2017 and June 2018, we established a cohort of 848 VPT infants and their parents from 60 English neonatal units. The study population (median (IQR), gestation: 28.9 (26-30) weeks; birth weight: 1120 (886-1420) g) represented 18.9% of eligible infants born at the study sites during the recruitment period (n=4491). From the subset of 521 complete family trios, we successfully completed genotyping for 510 (97.9%) trios. Of the original 883 infants whose parents consented to participate, the parents of 796 (90.1%) infants agreed to future data linkage and 794 (89.9%) agreed to be recalled. CONCLUSION: We demonstrate the feasibility and acceptability of streamlined strategies for genetic, neonatal and longitudinal data collection and provide a template for future cost-effective and efficient cohort development

Contribution of de novo and inherited rare copy number variants to very preterm birth

Background The genomic contribution to adverse health sequelae in babies born very preterm (<32 weeks’ gestation) is unknown. We conducted an investigation of rare CNVs in infants born very preterm as part of a study to determine the feasibility and acceptability of a larger, well-powered genome-wide investigation in the UK, with follow-up using linked National Health Service records and DNA storage for additional research. Methods We studied 488 parent–offspring trios. We performed genotyping using Illumina Infinium OmniExpress Arrays. CNV calling and quality control (QC) were undertaken using published protocols. We examined de novo CNVs in infants and the rate of known pathogenic variants in infants, mothers and fathers and compared these with published comparator data. We defined rare pathogenic CNVs as those consistently reported to be associated with clinical phenotypes. Results We identified 14 de novo CNVs, representing a mutation rate of 2.9%, compared with 2.1% reported in control populations. The median size of these CNV was much higher than in comparator data (717 kb vs 255 kb). The rate of pathogenic CNVs was 4.3% in infants, 2.7% in mothers and 2% in fathers, compared with 2.3% in UK Biobank participants. Conclusion Our findings suggest that the rate of de novo CNVs, especially rare pathogenic CNVs, could be elevated in those born very preterm. However, we will need to conduct a much larger study to corroborate this conclusion

The impact of schizophrenia and mood disorder risk alleles on emotional problems: investigating change from childhood to middle age

Previous studies find that both schizophrenia and mood disorder risk alleles contribute to adult depression and anxiety. Emotional problems (depression or anxiety) begin in childhood and show strong continuities into adult life; this suggests that symptoms are the manifestation of the same underlying liability across different ages. However, other findings suggest that there are developmental differences in the etiology of emotional problems at different ages. To our knowledge, no study has prospectively examined the impact of psychiatric risk alleles on emotional problems at different ages in the same individuals. Data were analyzed using regression-based analyses in a prospective, population-based UK cohort (the National Child Development Study). Schizophrenia and major depressive disorder (MDD) polygenic risk scores (PRS) were derived from published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessed prospectively at six time points from age 7 to 42 years. Schizophrenia PRS were associated with emotional problems from childhood [age 7, OR 1.09 (1.03–1.15), p = 0.003] to mid-life [age 42, OR 1.10 (1.05–1.17), p < 0.001], while MDD PRS were associated with emotional problems only in adulthood [age 42, OR 1.06 (1.00–1.11), p = 0.034; age 7, OR 1.03 (0.98–1.09), p = 0.228]. Our prospective investigation suggests that early (childhood) emotional problems in the general population share genetic risk with schizophrenia, while later (adult) emotional problems also share genetic risk with MDD. The results suggest that the genetic architecture of depression/anxiety is not static across development

Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study

Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991–2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1–15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness

Tumour boards in geriatric oncology

Multidisciplinary tumour board (MDT) is an integral part of cancer treatment planning. Although no definite survival benefits have yet been shown by mostly observational studies, other benefits of MDT have been identified. Traditionally the MDT involves participation of treating clinicians – medical, radiation and surgical oncologists. They tend to focus on the cancer alone. There is an increasing awareness that the treatment goal for cancer in older adults is not primarily on prolonging survival, with functional preservation and quality of life being particularly important for this population. The use of comprehensive geriatric assessment and the input of the geriatrician in informing the oncologists regarding treatment decision have increasingly been shown to be beneficial. The integration of the geriatrician into an MDT should be urgently explored

Tumour boards in geriatric oncology

Multidisciplinary tumour board (MDT) is an integral part of cancer treatment planning. Although no definite survival benefits have yet been shown by mostly observational studies, other benefits of MDT have been identified. Traditionally the MDT involves participation of treating clinicians – medical, radiation and surgical oncologists. They tend to focus on the cancer alone. There is an increasing awareness that the treatment goal for cancer in older adults is not primarily on prolonging survival, with functional preservation and quality of life being particularly important for this population. The use of comprehensive geriatric assessment and the input of the geriatrician in informing the oncologists regarding treatment decision have increasingly been shown to be beneficial. The integration of the geriatrician into an MDT should be urgently explored

A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

Recent case–control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD. Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200 kb) CNVs and identified those calls that were present in the proband and absent in both biological parents. In 305 parent–offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at four genomic loci (15q13.1–13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case–control ADHD studies. Our study complements ADHD case–control genomic analyses and demonstrates the need for larger parent–offspring trio genetic studies to gain further insights into the complex aetiology of ADHD

Investigating attention-deficit hyperactivity disorder and autism spectrum disorder traits in the general population:What happens in adult life?

Background. ADHD and ASD are generally considered early-onset disorders so most research has therefore tended to focus on children. Differences between ADHD/ASD in adult life and childhood have been noted, but few population-based studies have examined them in adulthood. Furthermore, interpretation of findings is hampered by changes in measure and from parent- to self-report. Method. We examined continuous/trait measures of parent- and self-rated ADHD and ASD) in adulthood (age 25 years) in a UK prospective longitudinal sample ALPSAC (the Avon Longitudinal Study of Parents and Children), using many of the same measures that parents reported on in childhood (N=6,064). Our aim was to investigate these traits in this population for mean-level sex differences, overlaps with other cognitive, learning and communication problems and their associations with polygenic risk scores (PRS) for neuropsychiatric disorders (ADHD, ASD, schizophrenia, depression and anxiety). Results. ADHD and ASD traits in adulthood, as in childhood, showed associations with childhood cognitive, learning and communication problems and with adult communication/language measures, although less so for self- than parent-ratings. Males had higher ADHD and ASD trait levels, but this was not as marked as in childhood. In adulthood, ADHD (both parent and self -rated) and ASD (parent-rated) symptoms showed associations with ADHD PRS; self-reported ADHD also showed association with depression PRS and self-reported ASD did not show strong PRS associations. Conclusions. Our findings suggest that in young adults, ADHD and ASD symptoms have similar characteristics as they do in in childhood. Associations with other cognitive, learning and communication problems, and with ADHD PRS, were somewhat less pronounced for self-reported adult ADHD and ASD symptoms, sugges

Investigating the genetic underpinnings of early-life irritability

Severe irritability is one of the commonest reasons prompting referral to mental health services. It is frequently seen in neurodevelopmental disorders that manifest early in development, especially attention-deficit/hyperactivity disorder (ADHD). However, irritability can also be conceptualized as a mood problem because of its links with anxiety/depressive disorders; notably DSM-5 currently classifies severe, childhood-onset irritability as a mood disorder. Investigations into the genetic nature of irritability are lacking although twin studies suggest it shares genetic risks with both ADHD and depression. We investigated the genetic underpinnings of irritability using a molecular genetic approach, testing the hypothesis that early irritability (in childhood/adolescence) is associated with genetic risk for ADHD, as indexed by polygenic risk scores (PRS). As a secondary aim we investigated associations between irritability and PRS for major depressive disorder (MDD). Three UK samples were utilized: two longitudinal population-based cohorts with irritability data from childhood (7 years) to adolescence (15–16 years), and one ADHD patient sample (6–18 years). Irritability was defined using parent reports. PRS were derived from large genome-wide association meta-analyses. We observed associations between ADHD PRS and early irritability in our clinical ADHD sample and one of the population samples. This suggests that early irritability traits share genetic risk with ADHD in the general population and are a marker of higher genetic loading in individuals with an ADHD diagnosis. Associations with MDD PRS were not observed. This suggests that early-onset irritability could be conceptualized as a neurodevelopmental difficulty, behaving more like disorders such as ADHD than mood disorders