WRITE A NOTE ON GENETIC EPIDEMIOLOGICAL STUDIES IN PSYCHIATRY ?
A 1 GENETIC EPIDEMIOLOGY
I - Genetic epidemiology includes -
A ) family and
B ) twin studies **
Vv imp - A ) 1 Family studies compare rates of illness in relatives of those who have the condition (case probands) with rates in relatives of healthy controls.
2 Higher rates in the former group of relatives, as parameterized by a relative risk (RR) or odds ratio (OR) greater than 1.0, suggest familial aggregation ( v imp )
B ) The next step relies on either adoption studies (which are not available for AD) or twin studies to differentiate genetic from within-family environment as sources of aggregation.
1 Twin studies compare resemblance for a condition between members of a twin pair using the fact that identical (monozygotic [MZ]) twins share 100% of their genes while non-identical (dizygotic [DZ]) twins share only 50% of their genes on average.
2 One commonly used measure of twin resemblance is the proband-wise concordance, that is, the proportion of co-twins of affected index twins who are also affected.
3 If average concordance for MZ pairs is greater than that for DZ pairs, this is evidence for a genetic component to family resemblance.
4 With larger twin samples, one may also estimate the proportion of individual differences due to the effects of genetic factors (heritability).
Vv imp 5 For conditions with substantial heritability, gene finding (linkage or association) studies are undertaken to identify which specific genes contribute to risk.
II - A 2001 meta-analysis summarized findings across extant family and twin studies for several individual or categories of adult AD
A ) Those results suggest an overall moderate level of familial aggregation (OR = 4–6) and heritability (30–50%) across the AD.
B ) Few family studies have been published since then, as it is now well-established that all AD moderately aggregate in families.
C ) More twin studies have been conducted, however, with emphasis on the cause of comorbidity or developmental risk.
III - Additive genetic effects (a2) represent the genetic component of variance due to the average effects of single alleles and are known as heritability
A ) shared environment effects (c2) are explained by events that happen to both twins, affecting them in the same way
B ) non-shared environment effects (e2) are explained by events that occur to one twin but not the other, or events that affect either twin in a different way.GAD, generalized anxiety disorder; PD, panic disorder; SAD, social anxiety
C ) As reviewed by Schumacher and colleagues, data from 19 controlled family studies overall support the familial aggregation of PD, with relative risk to first-degree relatives (FDR) ranging from 3 to 17
D ) Five of these meeting strict inclusion criteria were analyzed in the meta-analysis, the results of which showed a highly significant association between PD in the proband and PD in FDR.
1- The summary OR across the five studies was 5.0 (95% confidence int and the unadjusted aggregate risk based on 1356 total FDR of PD probands was 10.0%, compared to 2.1% in 1187 control relatives.
2 - Additionally, one study suggests higher familial risk associated with early-onset PD in the proband.
E ) The two largest sources of adult twin data for most of the AD ( alzheimer disease ) , including PD ( parkinson disease ) , are the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD), and the Vietnam Era Twin (VET) Registry.
1 The former consists of approximately 9000 twins from male and female same-sex and opposite-sex pairs born in Virginia, while the latter is of comparable size but contains only US male twins who served during the Vietnam War.
2 The size of these samples permits the use of structural equation modeling to assess the relative contributions of genetics, common family (shared) environment, and individual specific (non-shared) environment to the liability of PD.
3 Both samples reported higher MZ than DZ concordance, suggesting a genetic component to PD, consistent with some prior smaller twin studies.
4 Both VATSPSUD and VET studies estimated heritability of PD to lie between 30 and 40%. The remaining source of individual differences derived from individual specific environment not shared between twins.
5 In addition, the VATSPSUD found no evidence that genetic risk factors for PD significantly differ between men and women.
1 Two published family studies of GAD were included in the aforementioned meta-analysis.
2 Both studies, derived from clinical probands, supported the familial aggregation of GAD, and together they show a significant association between GAD in the probands and in their FDR, with a summary OR of 6.08 (95%CI: 2.5–14.9).
3Both the VATSPSUD and the VET Registry examined broadened GAD syndromes via twin analyses, with an overall heritability of 31.6% (95%CI: 24–39%) when data from both samples were combined via meta-analysis
1 Fyer and colleagues performed a series of analyses examining specific phobia, social phobia, and agoraphobia and their relation with each other and PD.
2 They reported higher rates of specific phobia in relatives of specific phobia probands compared with control relatives (31% vs 9%), higher rates of social phobia in relatives of social phobia probands (16% vs 5%), and higher rates of agoraphobia in relatives of agoraphobia probands (10% vs 3% )
3 Another family study reported higher rates of agoraphobia in relatives of probands with agoraphobia compared to control relatives (11.6% vs 4.2%, OR = 3.0 )
4 Two studies of social phobia found that familial aggregation is primarily due to the generalized sub-type. Meta-analysis across family studies found a highly significant association between phobias in the proband and in FDR, with a summary OR of 4.07 (95%CI: 2.7–6.1)
5 Only two large, adult twin samples have comprehensively examined the genetics of phobias in adults.
6 A series of analyses in the VATSPSUD examining phobic fears and disorders found that twin resemblance was due largely to genetic factors across agoraphobia, social phobia, and specific phobia, estimating that genetic factors explain from 30 to 60% of their individual differences.
7 Similar heritability estimates were reported from a study of about 1400 female twins from the Norwegian Institute of Public Health Twin Panel (NIPHTP).
8 A meta-analysis of five studies that included diagnoses of social anxiety disorder (SAD) suggested that genetic influence accounted for 27% of variance, while the rest was almost explained by non-shared environmental factors (69%).
9 The highest mean heritability among fear subtypes was animal fear (45%), and among specific phobias, the highest mean heritability was blood-injury-injection phobia (33%).
10 In both studies, variance for the phenotypes could be mainly explained by genetic and non-shared environmental effects.
11 To date, most association studies of AD have focused on candidate genes, which have to be chosen using a priori knowledge, either from their position under a linkage peak or their biologic function as relevant for the pathophysiology of the disease.
12 The most widely studied candidate genes for AD are genes involved in neurotransmitter systems (e.g., serotonin, norepinephrine, glutamate, and dopamine) or related to stress response.
13 In their review, Maron et al. summarized more than 350 candidate gene findings for PD, concluding that most of these results remain inconsistent, negative, or not clearly replicated.
A ) Failure to identify susceptibility loci in PD may be due to differences in phenotypic assessment, heterogeneity at the genetic level, and underpowered studies with small sample sizes.
B ) McGrath et al. conducted a systematic review of candidate gene studies for AD or anxiety symptom measures.
C ) When restricted to studies with a sample size of at least 200 cases, 65 reports were found.
1 - PD has been the most frequently studied disorder (n = 30), compared to GAD (n = 4), SAD (n = 1), and specific phobia (n = 1).
2 - The three most commonly studied genes were catechol-O-methyltransferase(COMT), serotonin transporter (SLC6A4, also known as 5-HTT), and brain-derived neurotrophic factor (BDNF).
3 - The largest studies examined SLC6A4 (1161 cases vs 1051 controls), with no consistent evidence of association with the 5-HTTLPR promoter variant.
4 - Furthermore, most complex disorders are believed to be highly polygenic and common variants underlying these disorders are expected to have modest effect sizes.
5 - Therefore, much larger sample sizes than those conducted in previous studies are required to detect reliable results.
III - Genome-wide association studies
A ) Unlike candidate gene studies, which require a priori knowledge for gene selection, genome-wide association studies (GWAS) provide an unbiased survey of common genetic variation across the entire genome. s 2578 controls), with no genome-wide significance
B ) Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex.
C ) They also demonstrated that TMEM132D *** was associated with anxiety-related behavior using a mouse model of extremes in trait anxiety.
D ) For other AD phenotypes, Hettema et al. investigated candidate gene associations in a sample with anxiety-related phenotypes, in which the candidate genes were selected from genome-wide anxiety-related genetic data in mice and humans.
1 The results suggested that the PPARGC1A gene, a transcriptional activator involved in normal energy expenditure and in metabolic conditions, was significantly associated with anxiety.
2 Although no genome-wide significance was found, the average estimates of heritability captured by the common variants were calculated as 10%, which was much lower than those reported in the previous twin studies.
ROLE OF GENETIC EPIDEMIOLOGY
1 Using family study method -
A ) to investigate causes of comorbidity of anxiety and depression
B ) provides stronger evidence for mood disorders in a same or same sub group of family
C ) examines the validity of the autism spectrum disorders (ASD).
D ) vv imp A review of these studies suggests that the most consistently familial traits in ASD are language and communication skills, insistence on sameness and non-verbal IQ.
E ) These are also the traits most commonly associated with the differentiation of autism from Asperger disorder and PDDNOS using both cross-sectional and longitudinal studies.
F ) From these data, a new classification system of the ASDs is proposed based on these familial traits.
2 - using twin - twin studies
Q 1 DISCUSS IN DETAIL PSYCHIATRIC EPIDEMIOLOGY ?
A 1 INTRODUCTION
1 Sociological studies ** of the early 20th century can be regarded as predecessors of today’s psychiatric epidemiology
A ) These studies investigated for instance how suicide rates differ between Protestant and Catholic countries or how the risk of suffering from schizophrenia is increased in neighborhood characterized with high levels of social isolation ( vv imp )
2 After World War 2 researchers began using community surveys to assess psychological problems.
A ) By the 1980s the development of new diagnostic assessment instruments and reliable criteria for mental disorders given by the DSM-3 began a trend to estimating the prevalence of mental disorders next to symptoms.
B ) As an example, in an attempt to measure the prevalence of mental illness in the United States, Lee Robins and Darrel A. Regier conducted a study called the Epidemiological Catchment Area Project which surveyed samples of the general population at five sites across America.
C ) In the study, it was found that about a third of all Americans suffer from mental illness at some point in their lives.
D ) This statistic is often referred to as lifetime prevalence **
3 Today, epidemiological studies focus on the **etiology of mental disorders, i.e. the identification and quantification of causes underlying psychiatric problems and their mechanisms, rather than mere estimation of prevalence.
A ) It is not ethically possible to experimentally expose study participants to stressors suspected to cause psychiatric disorders, thus epidemiological techniques are required to study the etiology.
B ) For this purpose longitudinal studies, which follow children and adults for a long period of time, often for many years, are particularly useful.
C ) These allow the study of naturally occurring exposures and how they affect changes in psychiatric symptoms.
D ) Two notable historical studies focusing on etiology are the Dunedin Multidisciplinary Health and Development Study and the Christchurch Health and Development Study ***
E ) These studies began in the 70’s and studied the impact of perinatal problems, genetic variants, sexual abuse and other adverse exposures on psychological problems in childhood and later in adulthood vv imp
4 Assessment of disorders
Many different instruments are used to assess mental disorders in epidemiological studies depending on the age of the participants, available recourses and other considerations.
A ) Studies featuring adolescents and adults often use structured interviewing, a technique in which a series of questions is administered by interviewers to determine whether an individual is disordered or nondisordered.
B ) Alternatively, questionnaire are used, which can be administered more easily.
C ) In epidemiological studies featuring children, psychopathology is often assessed using parent report, however, multi-informant approaches, e.g. the simultaneous use of parent, teachers and self-report, is popular as well.
1 Psychiatric epidemiology is a field which studies the causes (etiology) of mental disorders in society, as well as conceptualization and prevalence of mental illness.
2 It is a subfield of the more general epidemiology.
3 It has roots in sociological studies of the early 20th century.
4 However, while sociological exposures are still widely studied in psychiatric epidemiology, the field has since expanded to the study of a wide area of environmental risk factors, such as major life events, as well as genetic exposures.
5 Increasingly neuroscientific techniques like MRI are used to explore the mechanisms behind how exposures to risk factors may impact psychological problems and explore the neuroanatomical substrate underlying psychiatric disorders.
TYPES OF EXPOSURES TO BE DONE FOR PSYCHIATRIC EPIDEMIOLOGY
A ) Psychiatric disorders show substantial heritability according to twin studies.
B ) A meta-analysis of most twin-studies conducted found a combined heritability of 46% for psychiatric disorders.
C ) Given the large contribution of genetic variants on psychiatric disorders, one major focus of psychiatric epidemiology is psychiatric genetics.
D ) A combination of family and molecular studies are used within psychiatric epidemiology to uncover the effects of genetics on mental health.
E ) Twin studies estimate the influences of all genetic variants and effects, but, due to relying purely on relatedness information, are limited in explaining the specific genetic mechanisms and architecture underlying psychiatric traits.
F ) Molecular studies confirm findings from family studies that genetic variants can partly explain the occurrence of psychological problems, e.g. by quantifying the total contribution of common genetic variants.
G ) Furthermore an increasing number of specific genetic loci are being associated with psychiatric disorders in large genome-wide association studies
A ) Next to genetic exposures, a wide variety of environmental exposures are being studied as well, such as nutrition, urbanicity, stressful life events and bullying.
B ) In contrast to genetic studies, the investigation of environmental exposures of psychiatric problems face the question of reverse causality ****
C ) E.g., experiencing social stress might cause depression, however, being depressed might also worsen relationships with others and thus cause social stress ( vv imp )
D ) Finding an association between the occurrence of an environmental exposure and a disorder could be the result of either or both situations.
E ) Multiple strategies exist in psychiatric epidemiology to assess the direction of causality.
F ) One possibility is measuring the exposure and outcome multiple times.
A ) Brain development is a complex process that starts during the early stage of embryogenesis and continues into adulthood.
B ) Studies focusing on risk factors of exposure on early brain development, have found differences in brain anatomy in children of mothers that consumed marihuana compared to unexposed control subjects, emphasizing the importance of intrauterine risk factors in early brain development.
4 Population-based imaging studies
A ) Population-based imaging studies attempt to find neurobiological substrates to explain psychiatric symptomatology.
B ) These studies have mainly used magnetic resonance imaging (MRI) sequences to study the brain at a population scale:
1 MRI sequences can be used to noninvasively study structural (e.g. volumetric) brain differences between individuals.
2 Other examples of MRI sequences are functional MRI (fMRI), studying activational patterns of the brain and diffusion tensor imaging (DTI), measuring the development and integrity of white matter tacts, i.e. the wiring of the brain.
3 These techniques have been used at various developmental stages, examples for each stage are discussed below.
A ) Pediatric population
1 - Imaging studies in children showed a significant association between autistic traits and gyrification patterns (winding patterns) of the brain on structural magnetic resonance imaging (MRI)*** PMR GUYS THIS ONE FOR YOU
2 - DTI studies, focusing on white matter development, showed that cognitive ability in children is positively associated with white matter integrity, as expressed by fractional anisotropy (FA) vv imp
B ) Elderly population
***Population-based studies in a large elderly population found a significant association between vascular white matter disease and depressive symptoms.