As an offshoot of my previous post - I think this is an obvious question. I am speaking from a medical context and not from the standpoint of genealogy. DNA studies of human origins that I posted here in the past are also a valuable use of genomic material. The latter are common reasons why people send their DNA off for analysis. Another reason is to learn if they have certain disease susceptibilities and that is where the real problems come in.
The genetics of many major diseases causing significant mortality and morbidity were worked out before the genomic era. They are the typical heritable disorders and inborn errors of metabolism that are flagged in popular sites like 23 & Me. I can't imagine that there are many surprises when subscribers find out that they do not have a fatal error of metabolism as an adult. Most of the concern is about complex polygenic disorders that may or may not have a significant environmental factor and that also lead to significant morbidity and mortality. From a philosophical standpoint this is also an interesting group of illnesses because there are clear parallels between psychiatric disorders and what are typically considered usual medical problems like hypertension, coronary artery disease, asthma, and diabetes mellitus. For the past decade, the standard genomic approach to study these disorders has been to scan large groups of genomes looking for mutations associated with these disorders. Those analyses are complex.
I thought I would continue with some clear cut examples form my own genome to illustrate the polygenes behind both heritability of complex disorders as well as the polygenes behind my current chronic conditions.
The at risk condition is bipolar disorder. My mother had severe bipolar 1 disorder. That is why nobody in my family ever doubts that bipolar disorder or "diagnoses" exist in psychiatry. Bipolar disorder is not a subtle condition and it is currently fairly easy to diagnosis. I credit DSM technology with making this an easy to recognize diagnosis. That was not the case 2 generations ago. The treatment in those days was less clear and there were very few resources to treat people in their communities. Despite my mother's diagnosis none of my siblings or their offspring has been diagnosed with bipolar disorder or any mood disorder. One of the inquiries for my genome is whether or not there are any polygenes associated with a bipolar disorder diagnosis.
The methodology I used for this post was to export all of my 23&Me data to Promethease, a search and cataloging software that arranges specific SNPs by disease, medication, genes, and several additional classification parameters. Before this software was available - I was stuck looking up every rsID in PubMed. The processing time of my entire genome in Promethease was 133 seconds. All of the correlates posted below are from that data. The first graphic is for bipolar disorder risk (click to enlarge).
Ten SNPs associated with bipolar disorder were identified. The risk is modest 1.39-2x. A more interesting feature is the facts that some of the identified SNPs were protective against bipolar disorder. In some cases, the SNP identified had to be in association with another gene in order to create the risk. Ethnic groups are also noted in association with some of these SNPs to increase and decrease risk. Standard approaches to this in the literature are to construct equations with risk terms from identified SNPs to determine which of those equations is the best predictor of risk. A second approach that I will discuss in a subsequent post is to use neural networks to determine associations between the SNPs and quantitative estimates to determine risk. At a macro level, the lesson is that a person with a non-bipolar disorder phenotype can carry multiple SNPs that may confer risk for bipolar disorder.
What about actual disease phenotypes? I am fortunate enough to have several for analysis. The first and in many cases the most illustrative is asthma. I have had asthma since childhood with various diagnoses along the way. The first diagnosis was a misdiagnosis and that it was a psychosomatic condition and not really asthma. Then it was diagnosed as allergic asthma. Then it was exercise induced asthma. I have received just about every conceivable treatment for asthma including some that have been determined to not be effective. There was also the famous disproven mechanism of action (increased intracellular cAMP) that was used to explain the mechanism of action for theophylline. I had a long quiescent period of about 20 years where I did not require any medical treatment at all. That ended about 6 years ago when I developed an upper respiratory infection and I have had to take medications ever since. My experience with available treatments has generally been disappointing. The variable course of the illness seems to have a more significant effect. That is probably why most treated asthmatics are symptomatic and the clinical markers of illness are mostly subjective. I have several posts on asthma on this blog discussing why it is an ideal comparison disease to polygenic psychiatry disorders. What does my genome say? (click to enlarge)
I have one sibling and one offspring of a sibling with asthma. In this case the situation is more complicated - 47 SNPs with varying risk and qualifiers based on numerous contexts such as ethnicity, smoking status of the parents, exposure to allergens, medication responsiveness and others. I highlighted a couple of SNPs that show a very high risk compared to what was seen in the bipolar disorder - specifically an odds ratio of 7.84 and a 3-fold to 39-fold increase in risk. Like the bipolar disorder case - some of the polygenes decrease risk as well. There is no available level of data integration beyond that and no clear guidance in terms of therapy.
UpToDate has a brief chapter (1 ) on the genetics of asthma. The authors point out that it is a complex polygenic illness that in some cases depends on environmental interactions. Like pre-genomic twin and family studies in psychiatric disorders there is a range of heritability. The authors recommend genetic testing in patients with asthma only to exclude monogenic obstructive lung diseases that can be misdiagnosed as asthma, such as cystic fibrosis, primary ciliary dyskinesia, and alpha-1 antitrypsin deficiency. They see other genetic testing as useful at the heuristic but not at a clinical level. They point out that the study of asthma genetics is complicated by the lack of a gold standard test and the uneven application of clinical diagnostic criteria. That has led to a study of a number of asthma traits.
From a pharmacogenomics standpoint up to half of asthma patients do not respond well to initial pharmacotherapy and even then the response is quite variable. They review the strategies used for genetic analyses, including SNPs as mentioned here but do not comment on any specific SNPs. I had a previous post on genes and GWAS studies of asthma. They do name several genes. After reading this chapter it is clear that the parallels between asthma and major psychiatric disorders is clearer than ever. All of the features of complex psychiatric illness including polygenic inheritance, complex heritability, lack of a gold standard medical test, and a lack of or incomplete response to medication that also occurs with severe psychiatric disorders.
The final chronic condition is atrial fibrillation. I had an onset about 8 years ago and as long as I take flecainide - I have no atrial fibrillation. I had one grandparent with atrial fibrillation. The SNPs identified follow and it is similar to asthma except fewer identified SNPs. Multiple SNPs with associated conditions (embolic or ischemic stroke) and qualifiers.
Fifteen SNPs noted in my genome for atrial fibrillation. Some of these genes have bare bones information (GWAS = genome wide association study, OMIM = online Mendelian Inheritance in Man). There are complementary approaches that involve using other databases like the GWAS database. Searching atrial fibrillation in that database. identifies a number of genotypes that were not found in my genome (rs247617, rs2129977, rs2220427, and rs6843082) and one that was - rs6843082.
Clearly, the approach I have outlined about is an improvement over searching Medline and my genome for SNP correlates but below any threshold for being able to use this information for precision medicine. That means it is below any standard required to look at diagnosis, prevention, or treatment.
There is probably a lot of information even at this level that is sitting there under analyzed. From my own genome, the involvement of the cytokine system (interleukins are cytokines) with multiple SNPs affecting those genes is a case in point. Many asthmatics have multiple allergic conditions including atopy, eczema, urticaria, and episodic anaphylaxis. These same individuals will see allergists, get tested and learn that they are allergic to everything. Those associated conditions are currently treated as medical mysteries or symptomatically as they flare up occasionally. Are there deeper patterns in the immune system that have not been realized at this time? Give the complexity of this system, I think that there are.
One of the key questions is whether the identified genes are producing identifiable products. At that level the short answer is that current detailed genomic information is interesting from an academic perspective - but like genomic testing we are years away from clinical applications. I could see the shadows of some serious family illnesses in my DNA like systemic lupus erythematosus and diabetes mellitus. The reasons why my relatives developed these diseases and I did not is not clear at this time. I think most people might come to that same conclusion if they compare their personal genome with SNP markers of diseases.
With a few exceptions, it takes more than correlating mutations in your own DNA to what is known about those mutations across a much larger population and coming up with a diagnosis. It probably takes more than knowing the mutations exist. Multiple omics approaches might provide better information and I hope to post one one of those experiments soon and the result of that experiment in the case of selective serotonin reuptake inhibitor (SSRI) antidepressants will be shocking.
George Dawson, MD, DFAPA
1: Author: Barnes KC. Section Editors: Barnes, PJ; Raby BA, Deputy Editor: Hollingsworth H. Genetics of asthma. In: UpToDate Accessed on August 14, 2018.