Monthly Archives: March 2016

  • A Roster of Opus 23 Algorithms

    This is a current list of the multi-snp algorithms currently available in Opus 23. A few titles repeat, for the simple reason that two different algorithms, using different snps or genes, can result in a similar conclusion.  Algorithms can be quite complex: it is not uncommon for one algorithm to call another algorithm as part of its execution. Algorithms are discussed in the blog post describing the Opus 23 LUMEN app.

     

    Classic Genetics

    • AB blood group
    • Blood Type O
    • A blood group (genotype AO)
    • A blood group (genotype AA)
    • A1/A2 blood group
    • B blood group (genotype BO)
    • B blood group (genotype BB)
    • Rhesus (Rh) blood group
    • Secretor
    • Non Secretor
    • Slight PTC Taster
    • PTC Non-Taster
    • Kell K/k blood group carrier
    • Duffy blood group positive (Fy+/+) / higher total WBC count
    • Possible Yu-Zhi (YZ) constitution
    • Odor perception for β-ionone

    Neurodegenerative Disease

    • Prediction of enhanced hippocampal volume
    • APOE E3/E3 genotype
    • Probably APOE E2/E4 genotype, Possibly E1/E3
    • APOE E2/E4 Genotype
    • APOE E4/E4 genotype
    • APOE E4/- genotype
    • APOE E3/E4 genotype
    • Bi-carrier of the minor alleles of rs1049296 and rs1800562
    • APOE E1/E1 Genotype
    • APOE E2/E2 Genotype
    • APOE E2/E3 Genotype
    • GAB2 rs2373115 (CC) and rs1800562 with APOE E4
    • GAB2 rs75932628(TT) Substitution
    • One short form 5-HTTLPR
    • Two long form 5-HTTLPR
    • Increased risk of Parkinson’s Disease
    • Decreased risk of Parkinson’s Disease
    • Increased risk of Parkinson’s Disease
    • Risk of autism related syndrome
    • Risk of autism related syndrome
    • Increased risk of autism/ social communication issues
    • Risk of autism related syndrome
    • Risk of autism related syndrome
    • Increased risk of Alzheimer’s Disease
    • Decreased risk of Alzheimer’s disease
    • Early-onset Alzheimer’s Disease risk
    • Elevated brain and cerebrospinal fluid concentrations of kynurenic acid
    • Lower levels of Indoleamine 2,3-dioxygenase (IDO1) activity

    Mind/ Body

    • Dopamine beta hydroxylase levels
    • Heightened placebo effect
    • Oxytocin ‘loner/ social empath’ polymorphism
    • Decreased risk of Alzheimer’s disease
    • Increased risk of bipolar disorder
    • Impaired motor skills learning
    • Increased risk of high cortisol levels when under stress
    • Lower levels of platelet MAO
    • D2 receptor DRD2 A1/A2 polymorphism
    • For Hispanics, 9 times more likely to develop heroin addiction ; risk of bi-polar issues
    • Increased risk for panic disorder (1.7x more likely)
    • Risk and intensity of functional somatic syndromes (CFS, FM)
    • Normal pain sensitivity
    • Variance in ‘self-referential’ processing in the brain
    • Higher ‘g’ score (general cognitive ability)
    • Increased ‘process reward’ from staring at smiling faces

    Methylation

    • MTHFR Polymorphisms Affecting Enzyme Activity
    • Risk of asthma, ADHD and Parkinson’s disease from high histamine
    • Epistatic subtle variants in COMT activity and pain sensitivity
    • Higher B12 Levels
    • Approximately​ 50% reduction ​in tetrahydrobiopterin (BH4) production and total biopterins
    • Risk of methyl trapping from high-dose/ premature methylation supplementation

    Auto-Immune/ Inflammatory

    • ‘Outside-in’ versus ‘inside-out’ genesis of atopic dermatitis.
    • Significant autoimmune disorder risk (HLA-DRA)
    • Moderate autoimmune disorder risk (HLA-DRA)
    • Increase risk of rheumatoid arthritis
    • Decreased soluble adhesion factors
    • Risk of autoimmune disorder/ gluten sensitivity
    • Risk of autoimmune disorder/ gluten sensitivity
    • Lower disorder/ gluten sensitivity risk (HLA-DQA1)
    • C-Reactive Protein Genotypes, Nutritional Status and Inflammation
    • Increased risk of allergic asthma
    • HLA genotypes and haplotypes
    • Increased risk of Crohn’s disease
    • Reduced risk (0.26) of Crohn’s disease and ulcerative colitis
    • Risk of Crohn’s disease
    • Increased risk of cluster headaches
    • Increased risk of migraine without aura
    • Increased headache frequency/use of analgesics medication
    • Increased risk of several autoimmune diseases
    • Increased risk of chronic fatigue syndrome
    • Slightly higher risk (1.17) of atopic dermatitis
    • Normal susceptibility to development of childhood asthma
    • Significantly increased risk several autoimmune diseases
    • Increased risk of rheumatoid arthritis

    Diet and Lifestyle

    • Effects of TP53/ high fat diet on Type 2 diabetes and obesity
    • Any type of exercise results in weight loss
    • High energy exercise required for weight loss
    • Balanced diet works best
    • Benefits from low-fat diet
    • Problematic effects from high fat diet
    • Benefits from low-carb diet
    • Novelty-seeking behavior
    • Possible high pain sensitivity
    • Possible low pain sensitivity
    • CYP1A2 ‘slow metabolizer’ Caffeine sensitivity
    • Ethanol biodisposition
    • Slower response to the effects of alcohol
    • Normal/increased rate of aging, reduced risk of dementia
    • Increased risk of nicotine addiction/ depression and loneliness in men
    • Sun sensitivity: No freckles and tans

    Digestion

    • Increased risk of diarrhea-predominant irritable bowel syndrome in women
    • Increased risk of diarrhea-predominant irritable bowel syndrome
    • Blood group B non-secretor: Increased risk of pancreatitis and high lipase levels

    Female Health

    • 10x higher risk for endometriosis, 0.5x lower risk for endometrial cancer, 0.76x less cognitive impairment with age
    • Evidence of earlier onset of menarche/ breast development
    • Decreased risk of hypertensive disorder complicating pregnancy

    Male Health

    • Severe risk of testicular germ cell tumors
    • Significantly increased risk of male pattern baldness

    Aging Related

    • Multi-gene Evidence of Longevity
    • 30-40% increase in MnSOD activity in mitochondria
    • Age related macular degeneration
    • AMD/ antioxidant response genotype group 1
    • Increased risk of developing osteoarthritis
    • Bone mineral density
    • Reduced memory abilities
    • Effect of FOXO3 and CFH polymorphisms on longevity
    • Possibly increased longevity; increased risk of colorectal cancer
    • Increased lifespan, better response to chemotherapy
    • Significantly younger, healthier kidney function
    • No increased likelihood of Fuchs’ dystrophy

    Endocrine Related

    • Possible corticosteroid resistance/ high cortisol syndrome
    • SHBG Levels affecting serum testosterone

    Hereditary Metabolic

    • Serum vitamin D levels
    • Increased risk of elevated uric acid levels and gout
    • Hereditary Hemochromatosis
    • Increased risk of Alpha-1 Antitrypsin Deficiency
    • Lower levels of tetrahydrobiopterin
    • Reduced conversion of beta-carotene to retinol
    • Low carotenoid conversion/ Low macular pigment optical density
    • Probably lactose tolerant
    • Probably lactose intolerant
    • Significantly Increased risk of Type II Diabetes
    • Lower circulating levels of adiponectin
    • Single HLA-DQ8 haplotype: Significant risk of Type I Diabetes
    • Mild trimethylaminuria
    • Increased hypersensitivity response to non-steroidal anti-inflammatory drugs
    • Reduced obesity and type 2 diabetes risk
    • Increased risk of metabolic syndrome/ consequences
    • Lowered risk of obesity
    • Increase risk of obesity
    • Wet earwax/ normal body odor/ normal colostrum
    • Increased risk (1.74) of gout
    • Significantly lower arachidonic acid and linoleic acid levels and higher interleukin (IL)-6 levels
    • Increased risk of T2DM from decreased capacity to scavenge ROS
    • Increased risk of elevated uric acid levels and gout
    • Increased risk of primary biliary cirrhosis
    • Lower serum levels of vitamin B12
    • Higher serum levels of vitamin B12
    • Lower serum levels of magnesium

    Resistance/ Immunity

    • Increased risk of Candida carriage
    • Increased risk of human papillomavirus persistence
    • Resistance to Norwalk norovirus infection
    • Increased risk of heightened inflammatory response/ antibiotic-refractory Lyme arthritis

    Musculo-skeletal

    • Training spectrum and traits indicative of elite athlete status
    • Increased musculoskeletal pain from fibromyalgia and temporomandibular disorders
    • Lower risk of lumbar disc disease
    • Increased risk of muscle cramps upon exertion

    Cardiology

    • Risk of venous thromboembolism
    • Lower heart attack risk (59%) than average
    • Decreased blood pressure levels
    • 300% increased risk of venous thrombosis
    • Lower risk (35%) of a heart attack or cardiovascular incident
    • Risk of myocardial infarction
    • Increased risk of Atrial Fibrillation
    • Risk of myocardial infarction and aspirin resistance
    • Higher blood viscosity potential
    • Ratios of TC/HDL and LDL/HDL probably benefit from skimmed milk
    • Lower HDL levels
    • Celera GRS: Reduced risk of coronary artery disease.
    • Increased risk of hypertension, but better response to therapy
    • Decreased risk (0.78) of heart attack
    • Aneurysms, both brain and abdominal aortic
    • Risk of salt-sensitive hypertension
    • Ten fold higher risk for heart disease in hereditary hemochromatosis patients with SOD2 mutation

    Oncology

    • Adiponectin intermediate signaler
    • Increased risk of ER+ breast cancer
    • Significantly increased risk of breast cancer
    • Adiponectin low signaler
    • Progesterone receptor gene PROGINS haplotype
    • Evidence of decreased risk of ovarian cancer
    • Increased risk of thyroid cancer
    • Increased risk of skin cancer
    • Decreased risk of skin cancer
    • Significantly increased risk of prostate cancer
    • Increased risk of prostate cancer
    • Increased risk of prostate cancer
    • Increased susceptibility and worsened outcome in malignant melanoma
    • Increased surveillance for colorectal cancer recommended
    • Lower risk of oral and upper digestive cancer
    • Risk hereditary Breast/ Ovarian / Prostate Cancer Syndrome
    • Increased risk of various types of cancer
    • Increased risk of colorectal cancer
    • Decreased risk of “upper aerodigestive” cancers
    • Substantially increased odds of developing V617F-positive MPN
    • Slightly increased risk of colon cancer
    • Increased risk of rectal bleeding after radiation therapy for prostate cancer
    • Increased risk of ‘chemobrain’

    Detoxification

    • CYP2D6*8 double reduced metabolism
    • CYP2C9 poor metabolizer
    • Pseudocholinesterase deficiency
    • CYP2D6*7 double reduced metabolism
    • CYP2D6*41 decreased metabolism
    • CYP3A5 non-expressor
    • CYP2C19 Extensive or Ultra-Fast Metabolizer
    • CYP2D6*6A reduced metabolism
    • CYP2D6*6A poor metabolizer
    • CYP1A2 fast metabolizer
    • CYP2D6*8 reduced metabolism
    • CYP2D6*8 poor metabolizer
    • CYP2D6*10 reduced metabolism
    • CYP2D6*10 poor metabolizer
    • CYP2D6*9 double reduced metabolism
    • CYP2D6*2 normal metabolism
    • CYP2C9 Intermediate Metabolizer
    • NAT2 Slow Metabolizer
    • NAT2 Intermediate Metabolizer
    • NAT2 Rapid Metabolizer
    • CYP2C19 normal/rapid metabolizer
    • CYP2D6*39 Normal Metabolizer
    • Possible CYP3A5 non-expressor
    • GSTM1 ‘Null’ Genotype

    Pharmacogenomics

    • Preferred form(s) of B12 supplementation
    • Adverse response to inhalers (Advair, Ventolin, Albuterol)
    • Decreased response to chemotherapy
    • Lower chemoresistance to anticancer drugs mitoxantrone, methotrexate, doxorubicin and camptothecin-based anticancer drugs
    • Adverse response to chemotherapy [neutropenia/leucopenia] from 5-fluorouracil
    • Increased chemoresistance to anticancer drugs mitoxantrone, methotrexate, doxorubicin and camptothecin-based anticancer drugs
    • Breast cancer chemotherapy: risk of hematological and gastrointestinal toxicities
    • Gefinitib takers more susceptible (4.0) to diarrhea
    • Increased toxicity to methotrexate
    • Gastric cancer: better response to chemotherapy
    • Increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy
    • Poor warfarin metabolizer
    • Intermediate warfarin metabolizer
    • Abnormal statin metabolizer
    • Favorable response to statin therapy likely
    • Impaired NSAID drug metabolism
    • No benefit from bupropion treatment for smoking cessation
    • Poor metabolism of proton pump inhibitor drugs
    • Poor metabolism/ adverse effects risk from clopidogrel (Plavix)
    • Less benefit from cyclophosphamide therapy in breast cancer

    Algorithms are added to Opus 23 fairly regularly and we suspect this will continue well into the future.

    “An algorithm must be seen to be believed.” –Donald Knuth

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  • Decoding 23andMe ‘i’ Numbers

    23andMe currently reports over 600,000 SNPs in the genome explorer, which are analyzed by their custom 2014 v4 chip. The process used is genotyping, rather than sequencing. The former is cheaper and quicker, and targets specific parts of the genome that are known to have variants in some or many people; the latter is used to find out the code of nucleotide base pairs in a sequence (or continuous stretch) of DNA, the exome (the coding part of DNA), or all the DNA in the whole genome.

    Genotyping does not report on all possible insertions or deletions. In general, it only reports small changes, spanning only one or a few bases. Sequencing will check whether all the DNA code in a region is found in the usual configuration or whether there are any unknown insertions or deletions.

    23andMe doesn’t test for all the SNPs they report on, but might impute variants present on larger chips or in sequencing analysis, using a statistical method that allows researchers to fill in missing data. This may be the reason 23andMe say “This data has undergone a general quality review, however only a subset of markers have been individually validated for accuracy.” [1]

    An example of this might be RhD blood group status: If you have a double deletion (DD) at “i4001527” you are RhD negative, if you don’t have the double deletion (DI or II) you are Rh positive. This number is available from a search in the 23andMe explorer, but is not found in the raw data can be downloaded in an ASCII text file and used for uploading to Opus23 Pro.

    Most of the numbers representing SNPs in the 23andMe raw data begin with ‘rs’, which are reference SNP identifiers, or reference SNP cluster IDs. [2] These rsIDs are assigned and managed by dbSNP, the official database for short genetic variations. However some numbers in the 23andMe raw data begin with ‘i’, which is an internal number assigned by 23andMe for testing locations on the genome for various reasons. This includes SNPs where the probes used differ from the reference sequence.[3] Some ‘i’ numbers are SNPs that don’t have rsIDs: 23andMe maps the i-number to the chromosome position, and internally they map this number to anything else they need to know about the SNPs to put it on a chip (many of these SNPs come from the custom portion of the genotyping array). Other ‘i’ numbers relate to SNPs that could highlight a genetic mutation in a user which is related to significant health risks or genetic conditions. The FDA don’t want users to be able to find out that they have these problems without genetic counselling, except for under specific circumstances where the user has made a declaration that they understand the consequences of accessing this data and what it might mean. The FDA are currently seeking medical opinion on situations where genetic test results might be available directly to the user. Comments can be submitted online  to the FDA by March 31st 2016. All submissions must include reference to: “Docket No.  FDA-2015-N-4809 for `Patient and Medical Professional Perspectives on the Return of Genetic Test Results; Public Workshop; Request for Comments.’”

    How does Opus23 Pro deal with ‘i’ numbers?

    Opus23 Pro curators use the genomic location linked with the coded ‘i’ numbers to find the rsID (if one exists), and if relevant, the ‘i’ numbers are added to the Opus23 Pro SNP database, and a lookup is performed by the software when analysing a client’s raw data. The ‘i’ numbers are linked with the rsID in the software, and this gives the practitioner a reference for further research in published medical literature. Any significant genetic risk factors can be added to the client report and explained to the patient, along with genetic counselling as necessary.

    References:

    1. Web page: “How 23andMe Reports Genotypes” https://customercare.23andme.com/hc/en-us/articles/212883677-How-23andMe-Reports-Genotypes.  Accessed 3/5/16
    2. The NCBI Handbook [Internet]. 2nd edition. Bethesda (MD): National Center for Biotechnology Information (US); 2013-. Accessed 3/5/16

    3. 23andMe forum “23andMe upgrading to NCBI Build 37 coordinates on Aug. 1” https://www.23andme.com/you/community/thread/14308/6/ Accessed 3/5/16
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