Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington's Disease.

BACKGROUND
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown.


METHODS
We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by 1) constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders and of intelligence and 2) testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n = 5160) of patients with HD.


RESULTS
Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence.


CONCLUSIONS
Polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.


Supplementary Information
Supplementary Figure S1: Flow diagram showing how the sample used to test association between PRS and symptoms was derived.  Results in italics satisfy the Bonferroni corrected p-value cut-off 7.94 x 10 -4 (corrected for 63 possible PRS-phenotype comparisons), and results in bold satisfy the Bonferroni corrected p-value cut of 1.32 x 10 -4 (corrected for the 63 PRS-symptom comparisons and 6 PRS cut-offs). Primary symptom-PRS hypotheses (see text) are underlined.

Guidelines for the age at onset questionnaire for EHDN-HD Registry patients
This questionnaire will capture essential and detailed information on when signs and symptoms that may be related or unrelated to HD first appear. Use the suggested wording below as a guide, but ask any other questions you need to try and date the onset as accurately as possible. Ask the patient first, then the carer (explain to the carer at the beginning that you will give them a chance to state their views after you have first heard from the patient) and finally record your own judgement about onset, taking account of what has been said by both patient and carer, and also what you can find in the case notes (or any other independent sources of information). It is not uncommon to find a record by a genetic counsellor who saw the patient and noticed choreiform movements, or an interview with a relative who mentioned that the family think the patient is affected, and this information may pre-date the estimates of either the patient or the carer who is acting as your informant on this occasion. Use your own judgement about the evidence, but avoid making guesses based only on your own experience of how long the average patient would need to be affected to reach this stage in the illness.

1.
Motor symptoms: When did you first notice any motor symptoms of HD, such as fidgety movements or clumsiness? Can you remember a particular occasion when this happened and you first realised you might be developing the family illness? What were you doing at the time? Where were you? Did you mention it to anyone else? (Try to identify any landmark events in the patient's life around that time, such as holidays, births, marriages & deaths in the family, etc, which might help to anchor the onset date by asking whether the onset was before or after that particular landmark)

Depression:
Have you ever suffered from depression for a period of 4 weeks or more? Was there ever a time you felt so low that you thought about ending it all? Have you been treated with antidepressants? When was the first time this happened to you (doesn't necessarily have to have been medicated in the first or any subsequent instance)?

Irritability and aggression:
Have there been times when you were irritable, bad tempered or 'cranky' for a period of 4 weeks or more? Have you had difficulty keeping control of your temper? When did this begin? If so, how bad was the worst ever episode? Has there been overt aggression? If so when did this first occur?

Apathy:
Have you noticed any change in your level of motivation? For example, has there ever been a period of four weeks or more when you lost interest in things that usually matter to you, or could not be bothered with activities you usually enjoy, or needed pushing to get around to jobs that need to be done, or spent a lot of time sitting around doing nothing? Did this ever happen at a time when you were not also feeling depressed? When did you first notice this change?

5.
Perseverative or Obsessive/Compulsive behaviours: Have you ever been troubled by recurrent thoughts, fears or mental images that came back over and over again, or had urges to do something over and over (e.g. double-checking, counting things, or washing your hands repeatedly)? Or perhaps found yourself unable to stop thinking about something, so that friends said you were getting it out of proportion, or getting a 'bee in your bonnet'? If so, how bad was the worst ever episode? When was the first time this happened to you?
6. Presence of psychosis: Has the patient ever reported symptoms resembling schizophrenia e.g. paranoid thinking, delusions and hearing voices. If so when was the first episode?

7.
Cognitive symptoms: Have you ever noticed any problems with your memory, or your ability to concentrate on things? Have you found it more difficult than it used to be to organise things, or perhaps noticed that it takes longer to get things done nowadays? Has anybody commented on this, or maybe criticised your performance at work or when doing chores at home? Can you remember the first time this happened? (probe as above and look for evidence such as job changes etc. which might suggest early cognitive difficulties)