L John Horwood’s research while affiliated with University of Otago and other places

Background and Hypothesis Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated. Study Design Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci. Study Results We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy. Conclusions This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.

This file is the online supplement for the paper: Recruitment and retention of participants in longitudinal studies after a natural disaster.

Background Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented. Results Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E⁻¹¹). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults. Conclusions These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

Objective Long-term studies following disasters are rare. It is important to quantify long-term effects of disasters to determine impacts on populations over time. We therefore aim to report the long-term associations between exposure to the Canterbury earthquakes and common mental disorders, taking into account potential confounding factors. Methods The Christchurch Health and Development Study is a 40-year longitudinal study of a birth cohort of New Zealand children (635 males and 630 females). The Christchurch Health and Development Study includes 884 participants with data on earthquake exposure and mental health outcomes at ages 34 and 40 years. Rates of Diagnostic and Statistical Manual of Mental Disorders (4th ed.) disorders were measured categorically and using an expanded definition that included sub-syndromal symptoms. The current impact of the earthquakes is reported using 12-month prevalence data 7 years after the earthquakes. The cumulative impact of the earthquakes over the 7 years since onset is also reported. Results There was a linear trend towards increasing rates of disorder with increasing exposure to the earthquakes. After adjusting for covariates, the 12-month prevalence of anxiety disorder symptoms was significantly increased ( p = 0.003). The earthquakes were also associated with cumulative increases in symptoms of post-traumatic stress disorder ( p < 0.001), anxiety disorder ( p = 0.016), nicotine dependence ( p = 0.012), and the total number of disorders ( p = 0.039). Conclusion The Canterbury earthquakes were associated with persistent increases in Anxiety Disorder symptoms 7 years after their onset. The earthquakes were also associated with cumulative increases in symptoms of common psychiatric disorders. The magnitude of these effects is small, may no longer be clinically significant and has decreased over time.

Background Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analysed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented. Results Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analysed on Illumina Infinium MethylationEPIC 850K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by logistic regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls, top CpGs featuring clusters in ARID3A, SPATA33, and PLCH1. The canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E− 11) and 15 of the 20 CpGs most different between VLBW cases and controls showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). At 28 years, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing direction with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with multiple cardiovascular traits in adults. Conclusions These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

Background: Executive function difficulties are common among children born very preterm and/or very low birthweight (<1500 g; VLBW), but little is known about whether they persist into adulthood. Objectives: Examine the nature and pattern of self-reported executive functioning at 23 and 28 years of age using data from a national cohort study of adults born VLBW and a comparison group of same-age full-term (FT) born adults. Also examined were associations between executive function difficulties and socio-economic outcomes. Methods: All infants born VLBW in New Zealand during 1986 were prospectively included in an audit of retinopathy of prematurity (n = 413), with 250 (77% of survivors) followed to median age 28 years. A comparison group of FT adults was also recruited at age 23 and followed to 28 years (n = 100). Across both adult assessments, executive functioning was assessed using the Behaviour Rating Inventory of Executive Function-Adult Version (BRIEF-A) and analysed with semi-parametric models to examine the effects of age and group on executive function. Results: At 23 and 28 years, VLBW adults had increased risk of executive function impairment compared with FT adults in behaviour regulation (relative risk [CI] 2.37, 95% confidence interval (CI)1.27, 4.45), meta-cognition (RR 6.03, 95% CI 2.18, 16.78) and global functioning (RR 3.20, 95% CI 1.40, 7.28). Impaired global executive functioning was associated with lower socio-economic status (regression estimate [b] = -0.43, 95% CI -0.59, -0.27) and a reduced likelihood of home ownership by age 28 years (RR 0.98, 95% CI 0.96, 1.00), even after controlling for sex, ethnicity and parental socio-economic backgrounds for both groups. Conclusion(s): VLBW-born adults continue to experience more executive function difficulties in their everyday life relative to term controls at age 28 years. These difficulties were negatively associated with their socio-economic opportunities as young adults.

Oral health in Aotearoa New Zealand has improved in the last seven decades, but improvements among young children have stagnated in the last two. Four out of ten 5-year-olds are affected by caries and many pre-schoolers require dental treatment under general anaesthesia. We analysed data from two longitudinal studies, the Dunedin Multidisciplinary Health and Development Study and the Christchurch Health and Development Study. We compared their methods, cohort characteristics and childhood oral health findings and discuss their implications for policy, research, and practice. Age 5 dmft was obtained in the Dunedin Study from clinical examinations, and from School Dental Service records in the Christchurch Study. Findings were consistent with respect to childhood socioeconomic status, exposure to community water fluoridation, and maternal education. Despite overall improvements, caries rates remain relatively unchanged: dmft in these cohorts, measured in the 1970s–1980s, resemble New Zealand’s statistics for 5-year-olds in the 2000s. Notwithstanding the steep caries decline observed over the years, the caries distribution has shifted, whereby the greatest severity of disease is now concentrated among a smaller group of the most deprived children. Early childhood caries appears to be a useful indicator of deprivation that should inform interventions for those in greatest need.

Background: Antenatal corticosteroids (ACS) given to mothers with anticipated very preterm delivery are widely used and improve infant outcomes. Follow-up studies of the first trials of ACS have shown no adverse effects, but recently there have been concerns about possible longer-term harms. Objectives: We aimed to assess the relationship of ACS therapy to a range of physical health and welfare measures in a cohort of very low birthweight (VLBW; <1500 g) young adults. Methods: Population-based cohort follow-up study. All VLBW infants born in New Zealand in 1986 were included in a prospective audit of retinopathy of prematurity. Perinatal data collection included information on ACS. At 26-30 years, 250 of 323 (77%) survivors participated, 58% having received ACS, with 229 assessed in one centre, including cardiovascular, metabolic, respiratory and neurocognitive measures. Differences in outcome between those receiving/not receiving ACS were summarised by the mean difference for continuous outcomes supplemented by Cohen's d as a standardised measure of effect size (ES), and risk ratios (RRI) for dichotomous outcomes, adjusted for relevant covariates using generalised linear regression methods. Results: There were no or minimal adverse effects of receipt of ACS versus no receipt across a range of health and welfare outcomes, both for the full cohort (adjusted ES range d = 0.01-0.23; adjusted RR range 0.78-2.03) and for individuals with gestation <28 weeks (extremely preterm; EP), except for a small increase in rates of major depression. In EP adults, receipt of ACS was associated with a higher incidence of hypertension, but might have a small benefit for IQ. Conclusions: In this population-based VLBW cohort, we detected minimal adverse outcomes associated with exposure to ACS by the third decade of life, a similar result to the 30-year follow-up of participants in the first ACS trial. However, further follow-up is warranted.