Health Psychology. Michael Murray
is associated with disease.
In spite of the precision of the method, GWAS findings have been disappointing. There is a lack of consistency in findings across studies and the amount of variance explained in traits or diseases is very low. For example, known SNPs explain less than 2% of the variation in body mass index (BMI) despite the evidence of greater than 50% heritability from twin and family studies, a phenomenon termed ‘missing heritability’. Llewellyn et al. (2013) used a novel method (Genome-wide Complex Trait Analysis, GCTA) to estimate the total additive genetic influence due to common SNPs on whole-genome arrays. This study provided the first GCTA estimate of genetic influence on adiposity in children. Participants were from the Twins Early Development Study (TEDS), a British twin birth cohort. Selecting one child per family (n = 2,269), GCTA results from 1.7 million DNA markers were used to quantify the additive genetic influence of common SNPs. For direct comparison, a standard twin analysis in the same families estimated the additive genetic influence as 82%. GCTA explained 30% of the variance in BMI-SDS. These results indicate that 37% of the twin-estimated heritability (30/82%) were explained by additive effects of multiple common SNPs, which is indicative of a strong genetic influence on adiposity in childhood. To fully explain this ‘missing heritability’, larger sample sizes are required to improve statistical power. Also, most variants that are associated with obesity from current GWAS are correlational, not causative (Xia and Grant, 2013).
In discussing obesity, Marti and Ordovas (2011: 190) reflected on the lack of progress on the tenth anniversary of the publications that reported the initial human genome sequence: ‘It was stated that the complete genome sequence would “revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases.” Whereas this is probably true, the question remains about “when” and “how”’. Ten years later the situation remains the same, and it is apparent that the human genome project has yet to reach its full potential. New approaches are required to identify the causative genes for the late onset and progressive nature of most common diseases, complex traits, and the mechanism by which the environment can modulate genetic predisposition to commonly occurring diseases.
Genetic counselling
Genetic counselling provides patients or relatives at risk of an inherited disorder (such as certain types of cancer) with advice and support concerning the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning. The main elements of genetic counselling have been described by Harper (2010) as follows:
Diagnostic and clinical aspects
Documentation of family and pedigree information
Recognition of inheritance patterns and risk estimation
Communication and empathy
Information of available options and further measures
Support in decision-making and for decisions already taken.
During a first appointment, the counsellor will draw a family tree using information about grandparents, aunt/uncles, and cousins on both sides of the family.
When an inherited condition is diagnosed in an individual there are potential consequences for other family members. However, privacy legislation and ethical considerations restrict health professionals’ ability to communicate the diagnosis with other family members, and it is normally the person who first receives the diagnosis who is responsible for sharing the news with their relations. There are many possible barriers to sharing this information, including stigma, fear, guilt and shame (James et al., 2006).
Owing to the complexity of genetic counselling as an intervention, there have been few randomized controlled trials (RCTs) to evaluate it. A trial of telephone genetic counselling conducted in Australia obtained a non-significant treatment effect. Hodgson et al. (2016) conducted an RCT in six public hospitals to assess whether a telephone counselling intervention improved family communication about a new genetic diagnosis. Only 26% (142/554) of the intervention group relatives made contact with genetic services, compared with 21% (112/536) of the control group relatives (P = 0.40).
A systematic review by Mendes et al. (2016) examined the dissemination of information within families, finding it to be actively encouraged and supported by genetic counselling professionals, following guidelines and recommendations from professional bodies. People requiring support or showing difficulties can receive psycho-educational guidance and written information aids as ‘cues for action’. A more direct approach is for genetics services to send letters to at-risk relatives informing them of their risks and the availability of counselling services. According to Mendes et al. (2016), this direct approach is acceptable to relatives and effective in promoting clarification of relatives’ genetic status.
We now turn to consider the second of the three ‘dice of life’, epigenetics.
Epigenetics and Intergenerational Transmission
Epigenetics is the study of heritable changes in a chromosome other than changes in the underlying DNA sequence. The epigenetic inheritance system has been described as ‘soft inheritance’ in comparison to genetics, which is ‘hard inheritance’ (Mayr and Provine, 1980). The inheritance of traits in genetics occurs as a result of rare genetic mutations that involve DNA mutation, but selection is slow in making adaptations to the constantly changing environment. The soft inheritance system of epigenetics, on the other hand, is able to adapt to fluctuations in the environment, such as changes in nutrition, stress and toxins (Wei et al., 2015).
Epigenetics at the cellular level produces cell differentiation by determining the functional types of cell, such as hepatocytes in the liver, neurones in the brain, or skin cells, as well as influencing whether or not they become cancerous. Within the CNS, epigenetics are involved in various neurodegenerative disorders and physiological responses, such as Alzheimer’s disease, depression, schizophrenia, glioma, addiction, Rett syndrome, alcohol dependence, autism, epilepsy, multiple sclerosis and stress. As neurones are incapable of dividing and cannot be replaced after degeneration, epigenetic alterations that cause neuronal dysfunction have to be targeted and modified to prevent chronic kinds of neurodegeneration, which can prove fatal (Adwan and Zawia, 2013).
Epigenetic changes include DNA methylation and histone modification, both of which regulate gene expression without altering the linear sequence of DNA. DNA methylation adds methyl groups to the DNA molecule, which can change the activity of a DNA segment without changing the sequence. DNA methylation typically acts to repress or switch off gene transcription. DNA methylation is implicated in a wide range of processes, including chromosome instability, X-chromosome inactivation, cell differentiation, cancer progression and gene regulation. The flexibility in gene expression is seen early in childhood and can be demonstrated in identical twins, who, even when raised in the ‘same’ environment, can have a different expression of genes. Essentially, DNA methylation is a switch that switches genes in the genotype on or off to produce the phenotype, the human being we actually become, rather than the one determined by a random mix from the gene bank of ‘Mum and Dad’ (Figure 3.6).
Epigenetics can be viewed as a set of bridging processes between the genotype and the creation of the all-important phenotype – a phenomenon that changes the final outcome of a locus or chromosome without changing the underlying DNA sequence (Goldberg et al., 2007). We turn to consider the role of epigenetics in developmental plasticity and the ‘Foetal Origins Hypothesis’, which is concerned with the role of nutrition and malnutrition in healthy foetal development.
Developmental plasticity and the Foetal Origins Hypothesis
Malnutrition during foetal life and infancy have been linked to the development of coronary heart disease, stroke, Type 2 diabetes, hypertension, osteoporosis and certain cancers, including breast cancer. All of these conditions can originate through the developmental plasticity process of foetal life. Geographical studies led David Barker (2007) to propose the ‘Foetal Origins Hypothesis’,