Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders
. They are heritable
and etiologically related
behaviors that have been resistant ...to gene discovery efforts
. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.
Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and ...relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five ...different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10
, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10
, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10
, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10
, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
Objective:
Attention-deficit/hyperactivity disorder affects over 5% of children and is characterised by a persistent pattern of problems with focussing or maintaining attention and/or ...hyperactivity-impulsivity. The censusADHD Study is a richly phenotyped nationwide cohort of Australian children with attention-deficit/hyperactivity disorder. The overarching aims of the study are to examine attention-deficit/hyperactivity disorder medication utilisation patterns and treatment response, the impact of children’s attention and behavioural problems on caregivers, and costs related to attention-deficit/hyperactivity disorder.
Methods:
Families of potential attention-deficit/hyperactivity disorder cases aged between 6 and 11 years were identified using Pharmaceutical Benefits Scheme prescription records for attention-deficit/hyperactivity disorder medications held by Services Australia and sent a study information letter. Data were collected from 1574 primary caregivers via online survey in 2015, including the behavioural profile of the child, the child’s medication use and experiences with side effects and the impact of the child’s behaviour on the caregiver. Approximately 81% of caregivers also consented to record linkage of the child’s Pharmaceutical Benefits Scheme and Medicare Benefits Schedule claims to directly assess prescription dispensing history and health service usage to estimate costs to the family and Medicare health system.
Results:
Boys were diagnosed with attention-deficit/hyperactivity disorder earlier (p = 0.021), more likely to present as the combined and predominantly hyperactive subtypes (p = 0.001) and at higher risk of experiencing a school suspension (p < 0.001) or expulsion (p = 0.043). Overall, children presenting as the combined subtype had higher rates of psychiatric comorbidities (p < 0.001). Finally, prescription costs for each family and the Pharmaceutical Benefits Scheme significantly increased in the year following attention-deficit/hyperactivity disorder diagnosis (p < 0.001).
Conclusion:
Research examining the psychosocial and financial impact of attention-deficit/hyperactivity disorder on Australian children and their families is needed. Our findings demonstrate the importance of examining both gender and attention-deficit/hyperactivity disorder subtype presentation in future studies.
Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not ...clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.
The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a ...considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity.
A total of 1021 participants (41.0% female; aged 46.2 ± 10.6 years range 18-66) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire.
Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively.
Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.
Here we review the motivation for creating the enhancing neuroimaging genetics through meta‐analysis (ENIGMA) Consortium and the genetic analyses undertaken by the consortium so far. We discuss the ...methodological challenges, findings, and future directions of the genetics working group. A major goal of the working group is tackling the reproducibility crisis affecting “candidate gene” and genome‐wide association analyses in neuroimaging. To address this, we developed harmonized analytic methods, and support their use in coordinated analyses across sites worldwide, which also makes it possible to understand heterogeneity in results across sites. These efforts have resulted in the identification of hundreds of common genomic loci robustly associated with brain structure. We have found both pleiotropic and specific genetic effects associated with brain structures, as well as genetic correlations with psychiatric and neurological diseases.
Improvement in the polygenic score prediction of hippocampal volume, as power in the discovery GWAS increases. PRS may be thought of as weighted‐sum scores that summarize the results of the GWAS to a given level of significance, these results show the increased explanatory power of the GWAS for hipocampal volume as sample size increases.
Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal ...nature of these associations is uncertain.
To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.
Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.
Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.
Offspring birth weight from 18 studies.
Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.
In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
Objective:
The Australian Genetics of Bipolar Disorder Study is a nation-wide cohort of adults living with bipolar disorder. The study aims to detect the relationships between genetic risk, symptom ...severity, and the lifetime prevalence of bipolar disorder, treatment response and medication side effects, and patterns and costs of health care usage.
Methods:
A total of 6682 participants (68.3% female; aged 44.8 ± 13.6 years range = 18–90) were recruited in three waves: a nation-wide media campaign, a mail-out based on prescriptions for lithium carbonate and through the Australian Genetics of Depression Study. Participants completed a self-report questionnaire. A total of 4706 (70%) participants provided a saliva sample and were genotyped and 5506 (82%) consented to record linkage of their Pharmaceutical and Medicare Benefits Schedule data.
Results:
Most participants were living with bipolar I disorder (n = 4068) while 1622 participants were living with bipolar II disorder and 992 with sub-threshold bipolar disorder. The mean age of bipolar disorder diagnosis was 32.7 ± 11.6 years but was younger in bipolar I (p = 2.0E-26) and females (p = 5.7E-23). Excluding depression with onset prior to bipolar disorder diagnosis, 64.5% of participants reported one or more co-occurring psychiatric disorders: most commonly generalised anxiety disorder (43.5%) and posttraumatic stress disorder (20.7%). Adverse drug reactions were common and resulted in discontinuation rates ranging from 33.4% for lithium to 63.0% for carbamazepine.
Conclusion:
Our findings highlight the high rate of comorbidities and adverse drug reactions among adults living with bipolar disorder in the general Australian population. Future genomic analyses focus on identifying genetic variants influencing pharmacotherapy treatment response and side effects.
Professor Nicholas G. Martin, from QIMR Berghofer Medical Research Institute in Brisbane, Australia, is a world leader in the effort to understand the genetic architecture underlying disordered ...gambling. This article pays tribute to Nick and his almost two decades of gambling research, highlighting his many strengths, ranging from the use of ingenious recruitment approaches, twin study methods, genomewide association studies, to facilitating international collaborations.
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